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Understanding the environmental health and safety of nanomaterials (NanoEHS) is essential for the sustained development of nanotechnology. Although extensive research over the past two decades has elucidated the phenomena, mechanisms, and implications of nanomaterials in cellular and organismal models, the active remediation of the adverse biological and environmental effects of nanomaterials remains largely unexplored. Inspired by recent developments in functional amyloids for biomedical and environmental engineering, this work shows their new utility as metallothionein mimics in the strategically important area of NanoEHS. Specifically, metal ions released from CuO and ZnO nanoparticles are sequestered through cysteine coordination and electrostatic interactions with beta-lactoglobulin (bLg) amyloid, as revealed by inductively coupled plasma mass spectrometry and molecular dynamics simulations. The toxicity of the metal oxide nanoparticles is subsequently mitigated by functional amyloids, as validated by cell viability and apoptosis assays in vitro and murine survival and biomarker assays in vivo. As bLg amyloid fibrils can be readily produced from whey in large quantities at a low cost, the study offers a crucial strategy for remediating the biological and environmental footprints of transition metal oxide nanomaterials.

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Understanding nanoparticle-cell interaction is essential for advancing research in nanomedicine and nanotoxicology. Apart from the transcytotic pathway mediated by cellular recognition and energetics, nanoparticles (including nanomedicines) may harness the paracellular route for their transport by inducing endothelial leakiness at cadherin junctions. This phenomenon, termed as NanoEL, is correlated with the physicochemical properties of the nanoparticles in close association with cellular signalling, membrane mechanics, as well as cytoskeletal remodelling. However, nanoparticles in biological systems are transformed by the ubiquitous protein corona and yet the potential effect of the protein corona on NanoEL remains unclear. Using confocal fluorescence microscopy, biolayer interferometry, transwell, toxicity, and molecular inhibition assays, complemented by molecular docking, here we reveal the minimal to significant effects of the anionic human serum albumin and fibrinogen, the charge neutral immunoglobulin G as well as the cationic lysozyme on negating gold nanoparticle-induced endothelial leakiness in vitro and in vivo. This study suggests that nanoparticle-cadherin interaction and hence the extent of NanoEL may be partially controlled by pre-exposing the nanoparticles to plasma proteins of specific charge and topology to facilitate their biomedical applications.

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Alzheimer's disease (AD) is a major cause of dementia debilitating the global ageing population. Current understanding of the AD pathophysiology implicates the aggregation of amyloid beta (Aß) as causative to neurodegeneration, with tauopathies, apolipoprotein E and neuroinflammation considered as other major culprits. Curiously, vascular endothelial barrier dysfunction is strongly associated with Aß deposition and 80-90% AD subjects also experience cerebral amyloid angiopathy. Here we show amyloid protein-induced endothelial leakiness (APEL) in human microvascular endothelial monolayers as well as in mouse cerebral vasculature. Using signaling pathway assays and discrete molecular dynamics, we revealed that the angiopathy first arose from a disruption to vascular endothelial (VE)-cadherin junctions exposed to the nanoparticulates of Aß oligomers and seeds, preceding the earlier implicated proinflammatory and pro-oxidative stressors to endothelial leakiness. These findings were analogous to nanomaterials-induced endothelial leakiness (NanoEL), a major phenomenon in nanomedicine depicting the paracellular transport of anionic inorganic nanoparticles in the vasculature. As APEL also occurred in vitro with the oligomers and seeds of alpha synuclein, this study proposes a paradigm for elucidating the vascular permeation, systemic spread, and cross-seeding of amyloid proteins that underlie the pathogeneses of AD and Parkinson's disease.

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Environmental plastic wastes are potential health hazards due to their prevalence as well as their versatility in initiating physical, chemical, and biological interactions and transformations. Indeed, recent research has implicated the adverse effects of micro- and nano-plastics, including their neurotoxicity, yet how plastic particulates may impact the aggregation pathway and toxicity of amyloid proteins pertinent to the pathologies of neurological diseases remains unknown. Here, electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS) is employed to reveal the polymorphic oligomerization of NACore, a surrogate of alpha-synuclein that is associated with the pathogenesis of Parkinson's disease. These data indicate that the production rate and population of the NACore oligomers are modulated by their exposure to a polystyrene nanoplastic, and these cellular assays further reveal an elevated NACore toxicity in microglial cells elicited by the nanoplastic. These simulations confirm that the nanoplastic-NACore association is promoted by their hydrophobic interactions. These findings are corroborated by an impairment in zebrafish hatching, survival, and development in vivo upon their embryonic exposure to the nanoplastic. Together, this study has uncovered the dynamics and mechanism of amyloidogenesis elevated by a nanoplastic trigger, shedding a new light on the neurological burden of plastic pollution.

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Therapeutic peptides are a major class of pharmaceutical drugs owing to their target-binding specificity as well as their versatility in inhibiting aberrant protein-protein interactions associated with human pathologies. Within the realm of amyloid diseases, the use of peptides and peptidomimetics tailor-designed to overcome amyloidogenesis has been an active research endeavor since the late 90s. In more recent years, incorporating nanoparticles for enhancing the biocirculation and delivery of peptide drugs has emerged as a frontier in nanomedicine, and nanoparticles have further demonstrated a potency against amyloid aggregation and cellular inflammation to rival strategies employing small molecules, peptides, and antibodies. Despite these efforts, however, a fundamental understanding of the chemistry, characteristics and function of peptido-nanocomposites is lacking, and a systematic analysis of such strategy for combating a range of amyloid pathogeneses is missing. Here we review the history, principles and evolving chemistry of constructing peptido-nanocomposites from bottom up and discuss their future application against amyloid diseases that debilitate a significant portion of the global population.

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Neurodegenerative disorders pose a significant challenge to global healthcare, with Alzheimer's disease (AD) being one of the most prevalent forms. Early and accurate detection of amyloid-ß (Aß) (1-42) monomers, a key biomarker of AD pathology, is crucial for effective diagnosis and intervention of the disease. Current gold standard detection techniques for Aß include enzyme-linked immunosorbent assay and surface plasmon resonance. Although reliable, they are limited by their cost and time-consuming nature, thus restricting their point-of-care applicability. Here we present a sensitive and rapid colorimetric sensor for the detection of Aß (1-42) monomers within 5 min. This was achieved by harnessing the peroxidase-like activity of metal-loaded metal-organic frameworks (MOFs), specifically UiO-66-NH2, coupled with the strong affinity of Aß (1-42) to the MOFs. Various metal-loaded MOFs were synthesized and investigated, and platinum-loaded UiO-66-NH2 was identified as the optimal candidate for our purpose. The Pt-loaded UiO-66-NH2 sensor demonstrated detection limits of 2.76 and 4.65 nM Aß (1-42) monomers in water and cerebrospinal fluid, respectively, with a linear range from 0.75 to 25 nM (R2 = 0.9712), outperforming traditional detection techniques in terms of both detection time and complexity. Moreover, the assay was specific toward Aß (1-42) monomers when evaluated against interfering compounds. The rapid and cost-effective sensor may help circumvent the limitations of conventional detection methods, thus providing a promising avenue for early AD diagnosis and facilitating improved clinical outcomes.

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Rapid growth of amyloid fibrils via a seeded conformational conversion of monomers is a critical step of fibrillization and important for disease transmission and progression. Amyloid fibrils often display diverse morphologies with distinct populations, and yet the molecular mechanisms of fibril elongation and their corresponding morphological dependence remain poorly understood. Here, we computationally investigated the single-molecular growth of two experimentally resolved human islet amyloid polypeptide fibrils of different morphologies. In both cases, the incorporation of monomers into preformed fibrils was observed. The conformational conversion dynamics was characterized by a small number of fibril growth intermediates. Fibril morphology affected monomer binding at fibril elongation and lateral surfaces as well as the seeded conformational conversion dynamics at the fibril ends, resulting in different fibril elongation rates and populations. We also observed an asymmetric fibril growth as in our prior experiments, attributing to differences of two fibril ends in terms of their local surface curvatures and exposed hydrogen-bond donors and acceptors. Together, our mechanistic findings afforded a theoretical basis for delineating different amyloid strains-entailed divergent disease progression.

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Alzheimer's disease (AD) is a major cause of dementia inducing memory loss, cognitive decline, and mortality among the aging population. While the amyloid aggregation of peptide Aß has long been implicated in neurodegeneration in AD, primarily through the production of toxic polymorphic aggregates and reactive oxygen species, viral infection has a less explicit role in the etiology of the brain disease. On the other hand, while the COVID-19 pandemic is known to harm human organs and function, its adverse effects on AD pathobiology and other human conditions remain unclear. Here we first identified the amyloidogenic potential of 1058HGVVFLHVTYV1068, a short fragment of the spike protein of SARS-CoV-2 coronavirus. The peptide fragment was found to be toxic and displayed a high binding propensity for the amyloidogenic segments of Aß, thereby promoting the aggregation and toxicity of the peptide in vitro and in silico, while retarding the hatching and survival of zebrafish embryos upon exposure. Our study implicated SARS-CoV-2 viral infection as a potential contributor to AD pathogenesis, a little explored area in our quest for understanding and overcoming Long Covid.

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Delivering cancer therapeutics to tumors necessitates their escape from the surrounding blood vessels. Tumor vasculatures are not always sufficiently leaky. Herein, we engineer therapeutically competent leakage of therapeutics from tumor vasculature with gold nanoparticles capable of inducing endothelial leakiness (NanoEL). These NanoEL gold nanoparticles activated the loss of endothelial adherens junctions without any perceivable toxicity to the endothelial cells. Microscopically, through real time live animal intravital imaging, we show that NanoEL particles induced leakiness in the tumor vessels walls and improved infiltration into the interstitial space within the tumor. In both primary tumor and secondary micrometastases animal models, we show that pretreatment of tumor vasculature with NanoEL particles before therapeutics administration could completely regress the cancer. Engineering tumoral vasculature leakiness represents a new paradigm in our approach towards increasing tumoral accessibility of anti-cancer therapeutics instead of further increasing their anti-cancer lethality.

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Carbon-based nanomaterials (CNMs) have recently been found in humans raising a great concern over their adverse roles in the hosts. However, our knowledge of the in vivo behavior and fate of CNMs, especially their biological processes elicited by the gut microbiota, remains poor. Here, we uncovered the integration of CNMs (single-walled carbon nanotubes and graphene oxide) into the endogenous carbon flow through degradation and fermentation, mediated by the gut microbiota of mice using isotope tracing and gene sequencing. As a newly available carbon source for the gut microbiota, microbial fermentation leads to the incorporation of inorganic carbon from the CNMs into organic butyrate through the pyruvate pathway. Furthermore, the butyrate-producing bacteria are identified to show a preference for the CNMs as their favorable source, and excessive butyrate derived from microbial CNMs fermentation further impacts on the function (proliferation and differentiation) of intestinal stem cells in mouse and intestinal organoid models. Collectively, our results unlock the unknown fermentation processes of CNMs in the gut of hosts and underscore an urgent need for assessing the transformation of CNMs and their health risk via the gut-centric physiological and anatomical pathways.

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Uncarialines A-E (1-5), five undescribed monoterpene indole alkaloids, together with five known analogues were obtained from the stems of Uncaria rhynchophylla. Alkaloids 1-3 were unique 3,4-seco-tricyclic alkaloids with a 6/5/10 ring system, while 4 and 5 possessed a rare rearranged scaffold originated from corynantheine-type alkaloids with C-2/C-7 oxidation. Their structures were characterized by a comprehensive analysis of MS, NMR, and ECD. Their effects on blood clotting times of human plasma were evaluated and alkaloid 5 had a slight prolongation effect on both thrombin time and activated partial thromboplastin time (p < 0.001).

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The aggregation of amyloid beta (Aß) is a hallmark of Alzheimer's disease (AD), a major cause of dementia and an unmet challenge in modern medicine. In this study, we constructed a biocompatible metal-phenolic network (MPN) comprising a polyphenol epigallocatechin gallate (EGCG) scaffold coordinated by physiological Zn(II). Upon adsorption onto gold nanoparticles, the MPN@AuNP nanoconstruct elicited a remarkable potency against the amyloid aggregation and toxicity of Aß in vitro. The superior performance of MPN@AuNP over EGCG@AuNP was attributed to the porosity and hence larger surface area of the MPN in comparison with that of EGCG alone. The atomic detail of Zn(II)-EGCG coordination was unraveled by density functional theory calculations and the structure and dynamics of Aß aggregation modulated by the MPN were further examined by discrete molecular dynamics simulations. As MPN@AuNP also displayed a robust capacity to cross a blood-brain barrier model through the paracellular pathway, and given the EGCG's function as an anti-amyloidosis and antioxidation agent, this MPN-based strategy may find application in regulating the broad AD pathology beyond protein aggregation inhibition.

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Eleven monoterpenoid indole alkaloids, including three new ones, tabercrassines A-C (1-3), were isolated from the seeds of Tabernaemontana crassa. Tabercrassine A (1) is an ibogan-ibogan-type bisindole alkaloid which is formed by the polymerization of two classic ibogan-type monomers through a C3 unit aliphatic chain. Their structures were established by extensive analysis of HRESIMS, NMR, and ECD spectra. Cellular assays showed that alkaloids 1-3 all reduce Aß42 production and inhibit phospho-tau (Thr217), a new biomarker of Alzheimer's disease [AD] associated with BACE1-, NCSTN-, GSK3ß-, and CDK5-mediated pathways, suggesting these alkaloids' potential against AD.

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Objective:To analyze the application value of metagenomic next-generation sequencing (mNGS) in the detection of pathogenic bacteria in brain abscesses.Methods:The data of patients with brain abscess in Tianjin Huanhu Hospital from January 2019 to December 2021 were retrospectively analyzed. All patients underwent stereotaxic abscess puncture and drainage. According to the different methods of pathogen detection, they were divided into bacterial culture group (bacterial culture only) and mNGS group (bacterial culture with mNGS). The clinical symptoms, abscess site, bacterial culture and mNGS results, antibiotic application protocol and prognosis of the patients were analyzed. The bacterial detection results of the two groups were analyzed, and the antibiotic application and prognosis were compared. χ 2 test, exact probability method and Mann Whitney test were used to compare the difference between the two groups. Results:A total of 43 patients with brain abscess were enrolled, including 21 cases in bacterial culture group and 22 cases in mNGS group. The positive rate of bacteria culture group was 42.9% (9/21), the positive rate of bacteria culture group was 45.5% (10/22), and the positive rate of mNGS detection was 100% (22/22). Only 3 cases in the bacterial culture group could have a clear bacterial source, while 17 cases in the mNGS group could have a clear bacterial source according to the bacterial results, showing a significant statistical difference between the two groups (χ 2=19.69, P<0.001). The return time of bacterial culture was 7.0 (4.0,7.0) days, and the average return time of mNGS was 1.5 (1.5,1.5) days, the difference of bacterial return time between the two groups was statistically significant ( Z=0.00, P<0.001). The cost of antibiotic use in bacterial culture group was 24.00 (5.60,31.00) thousands yuan, and the cost of antibiotic use in mNGS group was 12.00 (2.10, 20.00) thousands yuan, and there was significant statistical difference between them ( Z=5.22, P=0.026). Conclusions:MNGS can quickly and accurately identify the types and sources of brain abscess pathogens, guide the clinical application of antibiotics more targeted, reduce the cost of antibiotic use, and is an effective method for the detection of brain abscess pathogenic bacteria.

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Objective:To investigate the clinical manifestations, pathogenesis,diagnosis and treatment of negative pressure hydrocephalus (NPH).Methods:A retrospective analysis was performed on the 5 patients with NPH admitted to the Department of Neurosurgery, Tianjin Huanhu Hospital from January 2019 to December 2021. All of the patients underwent lumbar puncture and ventricular puncture to test the pressure. Three patients underwent endoscopic third ventriculostomy (ETV), the outcome of the patients was observed.Results:The pressure of subarachnoid was not equal to intraventricular, and the pressure of intraventricular was negative. Cisternography showed cerebrospinal fluid circulation obstruction in all 5 cases. The symptoms of 1 patient were improved after external negative pressure drainage, 3 patients were improved after further ETV and 1 patient had pulmonary infection without further surgical treatment.Conclusion:With the obstruction of cerebrospinal fluid circulation, the pressure of lateral ventricle and subarachnoid is different, when the pressure of brain or subarachnoid drop, the ventricular expansion under the effect of pressure gradient, intraventricular pressure drop even for the negative pressure. CT cisternography provides strong evidence for the diagnosis of this disease. External ventricular drainage with negative pressure and ETV are effective treatment methods.

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BACKGROUND: The biological behavior of carcinoma of the esophagogastric junction (CEGJ) is different from that of gastric or esophageal cancer. Differentiating squamous cell carcinoma of the esophagogastric junction (SCCEG) from adenocarcinoma of the esophagogastric junction (AEG) can indicate Siewert stage and whether the surgical route for patients with CEGJ is transthoracic or transabdominal, as well as aid in determining the extent of lymph node dissection. With the development of neoadjuvant therapy, preoperative determination of pathological type can help in the selection of neoadjuvant radiotherapy and chemotherapy regimens. AIM: To establish and evaluate computed tomography (CT)-based multiscale and multiphase radiomics models to distinguish SCCEG and AEG preoperatively. METHODS: We retrospectively analyzed the preoperative contrasted-enhanced CT imaging data of single-center patients with pathologically confirmed SCCEG (n = 130) and AEG (n = 130). The data were divided into either a training (n = 182) or a test group (n = 78) at a ratio of 7:3. A total of 1409 radiomics features were separately extracted from two dimensional (2D) or three dimensional (3D) regions of interest in arterial and venous phases. Intra-/inter-observer consistency analysis, correlation analysis, univariate analysis, least absolute shrinkage and selection operator regression, and backward stepwise logical regression were applied for feature selection. Totally, six logistic regression models were established based on 2D and 3D multi-phase features. The receiver operating characteristic curve analysis, the continuous net reclassification improvement (NRI), and the integrated discrimination improvement (IDI) were used for assessing model discrimination performance. Calibration and decision curves were used to assess the calibration and clinical usefulness of the model, respectively. RESULTS: The 2D-venous model (5 features, AUC: 0.849) performed better than 2D-arterial (5 features, AUC: 0.808). The 2D-arterial-venous combined model could further enhance the performance (AUC: 0.869). The 3D-venous model (7 features, AUC: 0.877) performed better than 3D-arterial (10 features, AUC: 0.876). And the 3D-arterial-venous combined model (AUC: 0.904) outperformed other single-phase-based models. The venous model showed a positive improvement compared with the arterial model (NRI > 0, IDI > 0), and the 3D-venous and combined models showed a significant positive improvement compared with the 2D-venous and combined models (P < 0.05). Decision curve analysis showed that combined 3D-arterial-venous model and 3D-venous model had a higher net clinical benefit within the same threshold probability range in the test group. CONCLUSION: The combined arterial-venous CT radiomics model based on 3D segmentation can improve the performance in differentiating EGJ squamous cell carcinoma from adenocarcinoma.

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Soluble oligomers populating early amyloid aggregation can be regarded as nanodroplets of liquid-liquid phase separation (LLPS). Amyloid peptides typically contain hydrophobic aggregation-prone regions connected by hydrophilic linkers and flanking sequences, and such a sequence hydropathy pattern drives the formation of supramolecular structures in the nanodroplets and modulates subsequent fibrillization. Here, we studied LLPS and fibrillization of coarse-grained amyloid peptides with increasing flanking sequences. Nanodroplets assumed lamellar, cylindrical micellar, and spherical micellar structures with increasing peptide hydrophilic/hydrophobic ratios, and such morphologies governed subsequent fibrillization processes. Adding glycine-serine repeats as flanking sequences to Aß16-22, the amyloidogenic core of amyloid-ß, our computational predictions of morphological transitions were corroborated experimentally. The uncovered inter-relationships between the peptide sequence pattern, oligomer/nanodroplet morphology, and fibrillization pathway, kinetics, and structure may contribute to our understanding of pathogenic amyloidosis in aging, facilitate future efforts ameliorating amyloidosis through peptide engineering, and aid in the design of novel amyloid-based functional nanobiomaterials and nanocomposites.

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The global-scale production of plastics has been instrumental in advancing modern society, while the rising accumulation of plastics in landfills, oceans, and anything in between has become a major stressor on environmental sustainability, climate, and, potentially, human health. While mechanical and chemical forces of man and nature can eventually break down or recycle plastics, our understanding of the biological fingerprints of plastics, especially of nanoplastics, remains poor. Here we report on a phenomenon associated with the nanoplastic forms of anionic polystyrene and poly(methyl methacrylate), where their introduction disrupted the vascular endothelial cadherin junctions in a dose-dependent manner, as revealed by confocal fluorescence microscopy, signaling pathways, molecular dynamics simulations, as well as ex vivo and in vivo assays with animal model systems. Collectively, our results implicated nanoplastics-induced vasculature permeability as primarily biophysical-biochemical in nature, uncorrelated with cytotoxic events such as reactive oxygen species production, autophagy, and apoptosis. This uncovered route of paracellular transport has opened up vast avenues for investigating the behaviour and biological effects of nanoplastics, which may offer crucial insights for guiding innovations towards a sustainable plastics industry and environmental remediation.

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The nanomaterial­protein "corona" is a dynamic entity providing a synthetic­natural interface mediating cellular uptake and subcellular distribution of nanomaterials in biological systems. As nanomaterials are central to the safe-by-design of future nanomedicines and the practice of nanosafety, understanding and delineating the biological and toxicological signatures of the ubiquitous nanomaterial­protein corona are precursors to the continued development of nano­bio science and engineering. However, despite well over a decade of extensive research, the dynamics of intracellular release or exchange of the blood protein corona from nanomaterials following their cellular internalization remains unclear, and the biological footprints of the nanoparticle­protein corona traversing cellular compartments are even less well understood. To address this crucial bottleneck, the current work screened evolution of the intracellular protein corona along the endocytotic pathway from blood via lysosomes to cytoplasm in cancer cells. Intercellular proteins, including pyruvate kinase M2 (PKM2), and chaperones, displaced some of the initially adsorbed blood proteins from the nanoparticle surface, which perturbed proteostasis and subsequently incited chaperone-mediated autophagy (CMA) to disrupt the key cellular metabolism pathway, including glycolysis and lipid metabolism. Since proteostasis is key to the sustainability of cell function, its collapse and the resulting CMA overdrive spell subsequent cell death and aging. Our findings shed light on the consequences of the transport of extracellular proteins by nanoparticles on cell metabolism.

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