The risk factors for chronic cough in children: a meta-analysis covering five continents.

BACKGROUND: This study aimed to explore the risk factors for chronic cough in children and provide a reference for prevention and healthcare measures. METHODS: PubMed, Web of Science, Cochrane, and EMBASE were searched for observational studies published up to April 2024. Outcome included risk factors associated with chronic cough in children. Two investigators independently searched and screened the literature, evaluated the qualities and extracted baseline datas. Results were analyzed using random-effects models with odds ratios and their 95% confidence intervals to address heterogeneity. Subgroup analyses, sensitivity analyses and assessment of publication bias were performed. Stata17 and GRADEwas used for the meta-analysis. RESULTS: 18 studies including 97,462 children were reviewed. Asthma( OR= 4.06, 95%CI: 2.37-6.96, P＜0.01), NO2( OR= 1.19, 95%CI: 1.01-1.39, P= 0.031), Home remodeling history ( OR= 1.82,95% CI: 1.61-2.05, P＜0.01), Environment Tobacco Smoke( OR= 1.41, 95% CI: 1.15-1.73, P=0.001), Pet exposure ( OR= 1.56, 95%CI: 1.25-1.95, P＜0.01), Mould (OR= 1.64,95%CI: 1.45-1.85, P＜0.01), Age＜1 year(OR= 3.19, 95% CI: 1.8-5.63, P＜0.01) were reported as risk factors for chronic cough in children, these results were discussed qualitatively in the study. CONCLUSION: Asthma, NO2, Home remodeling history, Environment Tobacco Smoke( ETS), Pet exposure, Mould, and Age＜1 year are risk factors for chronic coughing in children. Due to the few studies and insufficient evidence, other potential risk factors need to be robustly confirmed by subsequent large-sample and multicenter trials.

Monitoring nonlinear large gradient subsidence in mining areas through SBAS-InSAR with PUNet and Weibull model fusion.

The subsidence of the earth's surface in mining areas is characterized by fast speed and large gradients. Conventional small baseline subset interferometric synthetic aperture radar (SBAS-InSAR) monitoring can significantly underestimate results, making it challenging to capture the surface's temporal subsidence features. In this context, this paper proposes a method for monitoring subsidence in mining areas. It utilizes a phase unwrapping network (PUNet) and a fused Weibull model within the SBAS-InSAR framework to address nonlinear and large-gradient subsidence. The basic principle of this method is to first process the SAR images using the small baseline method to obtain the differential interferogram, utilizing the PUNet to obtain reliable large-gradient unwrapped phases. Next, the Weibull model parameters of each pixel are calculated based on the unwrapped phase, and the temporal subsidence of each point on the surface is determined using the calculated parameters. This method introduces a nonlinear model into the SBAS-InSAR solution, which is more consistent with the subsidence characteristics of mining areas. Through experimentation in a backfilled mining working face, the proposed method in this paper yields superior monitoring results compared to conventional approaches.

Impaired intestinal FXR signaling is involved in aberrant stem cell function leading to intestinal failure-associated liver disease in pediatric patients with short bowel syndrome.

Intestinal failure-associated liver disease (IFALD) is a serious complication of long-term parenteral nutrition in patients with short bowel syndrome (SBS), and is the main cause of death in SBS patients. Prevention of IFALD is one of the major challenges in the treatment of SBS. Impairment of intestinal barrier function is a key factor in triggering IFALD, therefore promoting intestinal repair is particularly important. Intestinal repair mainly relies on the function of intestinal stem cells (ISC), which require robust mitochondrial fatty acid oxidation (FAO) for self-renewal. Herein, we report that aberrant LGR5+ ISC function in IFALD may be attributed to impaired farnesoid X receptor (FXR) signaling, a transcriptional factor activated by steroids and bile acids. In both surgical biopsies and patient-derived organoids (PDOs), SBS patients with IFALD represented lower population of LGR5+ cells and decreased FXR expression. Moreover, treatment with T-ßMCA in PDOs (an antagonist for FXR) dose-dependently reduced the population of LGR5+ cells and the proliferation rate of enterocytes, concomitant with decreased key genes involved in FAO including CPT1a. Interestingly, however, treatment with Tropifexor in PDOs (an agonist for FXR) only enhanced FAO capacity, without improvement in ISC function and enterocyte proliferation. In conclusion, these findings suggested that impaired FXR may accelerate the depletion of LGR5 + ISC population through disrupted FAO processes, which may serve as a new potential target of preventive interventions against IFALD for SBS patients.

Correction: Specific transfection of inflamed brain by macrophages: A new therapeutic strategy for neurodegenerative diseases.

[This corrects the article DOI: 10.1371/journal.pone.0061852.].

Epidemiologic trends and changes in humoral immunity and lymphocyte subsets levels among hospitalized children with Mycoplasma pneumoniae infection during 2019-2023.

PURPOSE: To understand the changes in humoral immunity and lymphocyte subsets levels among hospitalized children with Mycoplasma pneumoniae (MP) infection from 2019 to 2023. METHODS: This study retrospectively analyzed inpatients aged 0-14 years who were diagnosed with MP infection or MP pneumonia in a tertiary hospital from January 2019 to December 2023. The children were divided into three groups: before the implementation of nonpharmaceutical interventions (NPIs), during the implementation of NPIs, and after the NPIs being lifted. RESULTS: A total of 4103 patients were enrolled in this study, of whom 2125 were diagnosed with MP infection and 1978 were diagnosed with MP pneumonia. The number of MP infection cases dramatically decreased early during the implementation of NPIs, and the previous epidemic trend resumed after the NPIs were lifted, with the number of cases during the period 2019-2023 peaked in November 2023. In children aged < 5 years, the levels of IgA and IgM and the percentages of total T cells and cytotoxic T cells in the "before the implementation of NPIs" group were greater than those in the other groups, and the percentage of total B cells was lower than that in the other groups. In children aged ≥ 5 years, the IgM level in the "before the implementation of NPIs" group was greater than that in the other groups. CONCLUSION: The number of MP-infected hospitalized children decreased significantly after NPI implementation and reached its highest peak during 2019-2023 in November 2023. After the NPIs were lifted, the level of humoral immunity was decreased and balance lymphocyte subsets were disrupted, especially in children aged < 5 years. We should pay close attention to and prevent MP infection in a timely manner after epidemics caused by large respiratory pathogens.

New Butterfly-Shaped Naphthalimide-Based AIE Gens: Synthesis and Photophysical Properties.

Two novel naphthalimide derivatives PTZNI-Cz and PTZNI-TPA were successfully designed and synthesized, in which phenothiazine, triphenylamine and carbazole were used as electron donors and naphthalimide was used as the electron acceptor. Their photophysical, electrochemical, and thermal properties were investigated. These derivatives showed remarkable aggregation-induced emission (AIE) effect. Furthermore, the maximum emission peaks of PTZNI-Cz and PTZNI-TPA in the thin film state are at 610 nm and 623 nm respectively, which is typical of red fluorescent materials.

RNA damage compartmentalization by DHX9 stress granules.

Biomolecules incur damage during stress conditions, and damage partitioning represents a vital survival strategy for cells. Here, we identified a distinct stress granule (SG), marked by dsRNA helicase DHX9, which compartmentalizes ultraviolet (UV)-induced RNA, but not DNA, damage. Our FANCI technology revealed that DHX9 SGs are enriched in damaged intron RNA, in contrast to classical SGs that are composed of mature mRNA. UV exposure causes RNA crosslinking damage, impedes intron splicing and decay, and triggers DHX9 SGs within daughter cells. DHX9 SGs promote cell survival and induce dsRNA-related immune response and translation shutdown, differentiating them from classical SGs that assemble downstream of translation arrest. DHX9 modulates dsRNA abundance in the DHX9 SGs and promotes cell viability. Autophagy receptor p62 is activated and important for DHX9 SG disassembly. Our findings establish non-canonical DHX9 SGs as a dedicated non-membrane-bound cytoplasmic compartment that safeguards daughter cells from parental RNA damage.

Understanding the Positive Role of Ionic Liquids in CO2 Capture by Poly(ethylenimine).

CO2 capture technology is one of the most important technical methods for significantly mitigating CO2 emissions in a low-carbon context. The recent invention of mixed absorbents comprising poly(ethylenimine) (PEI) and ionic liquids (ILs) provides a novel strategy for efficiently capturing CO2, and this has garnered widespread attention. However, the intermolecular interactions between the IL and other constituents during the CO2 absorption process remain unclear. In this present work, a series of density functional theory (DFT) calculations and molecular dynamics simulations were conducted to investigate the positive role of IL in CO2 capture by PEI. The results showed that the formation of hydrogen bonds between the IL anion and the amino groups of PEI primarily drives the addition of IL to PEI. During the CO2 absorption process, the IL anion not only can absorb CO2 but also exerts a dehydrogenation effect on the amino group of PEI, facilitating enhanced interaction between PEI and CO2. Additionally, the IL substantially reduces the viscosity of PEI, promoting the diffusion of CO2 within the system and enhancing the absorption rate. Based on the information on interaction energy and viscosity, we can easily make theoretical predictions for the optimal proportion of IL to be added. The above results provide fundamental insights to promote the industrial application of the PEI/IL system for CO2 capture.

Hollow Plasmonic P-Metal-N S-Scheme Heterojunction Photoreactor with Spatially Separated Dual Cocatalysts toward Artificial Photosynthesis.

Semiconductor-based step-scheme (S-scheme) heterojunctions possess many merits toward mimicking natural photosynthesis. However, their applications for solar-to-chemical energy conversion are hindered by inefficient charge utilization and unsatisfactory surface reactivity. Herein, two synergistic protocols are demonstrated to overcome these limitations based on the construction of a hollow plasmonic p-metal-n S-scheme heterojunction photoreactor with spatially separated dual noble-metal-free cocatalysts. On one side, plasmonic Au, inserted into the heterointerfaces of CuS@ZnIn2 S4 core-shell nanoboxes, not only accelerates the transfer and recombination of useless charges, enabling a more thorough separation of useful ones for CO2 reduction and H2 O oxidation but also generates hot electrons and holes, respectively injects them into ZnIn2 S4 and CuS, further increasing the number of active carriers participating in redox reactions. On the other side, Fe(OH)x and Ti3 C2 cocatalysts, separately located on the CuS and ZnIn2 S4 surface, enrich the redox sites, adjust the reduction potential and pathway for selective CO2 -to-CH4 transformation, and balance the transfer and consumption of photocarriers. As expected, significantly enhanced activity and selectivity in CH4 production are achieved by the smart design along with nearly stoichiometric ratios of reduction and oxidation products. This study paves the way for optimizing artificial photosynthetic systems via rational interfacial channel introduction and surface cocatalyst modification.

Targeting GPX4-mediated Ferroptosis Alleviates Liver Steatosis in a Rat Model of Total Parenteral Nutrition.

BACKGROUND: Parenteral nutrition-associated liver disease (PNALD) is a common hepatobiliary complication resulting from long-term parenteral nutrition (PN) that is associated with significant morbidity and mortality. Ferroptosis plays a significant role in the pathogenesis of various liver diseases. This study aims to explore the role of ferroptosis in PNALD and to uncover its underlying mechanisms. METHODS: Ferroptosis was evaluated in pediatric patients with PNALD and in rats administered with total parenteral nutrition (TPN) as an animal model of PNALD. In TPN-fed rats, we applied liproxstatin-1 (Lip-1) to inhibit ferroptosis for 7 days and assessed its impact on liver steatosis. We performed RNA-seq analysis to profile the alterations in miRNAs in livers from TPN-fed rats. The ferroptosis-promoting effects of miR-431 were evaluated in HepG2 cells and the direct targeting effects on glutathione peroxidase 4 (GPX4) were evaluated in HEK293T cells. RESULTS: RNA-seq analysis and experimental validation suggested that ferroptosis was increased in the livers of pediatric patients and rats with PNALD. Inhibiting ferroptosis with Lip-1 attenuated liver steatosis by regulating PPARα expression. RNA-seq analysis uncovered miR-431 as the most upregulated miRNA in the livers of TPN-fed rats, showing a negative correlation with hepatic GPX4 expression. In vitro studies demonstrated that miR-431 promoted ferroptosis by directly binding to the 3'UTR of GPX4 mRNA, resulting in the suppression of its expression. CONCLUSIONS: Our study demonstrates that TPN induces the upregulation of miR-431 in rats, leading to activation of ferroptosis through downregulation of GPX4. Inhibition of ferroptosis attenuates TPN-induced liver steatosis by regulating PPARα expression.

Unveiling the Nature of Superior Sodium Storage in the CoSe2/rGO Nanocomposite.

Sodium-ion batteries (SIBs) are considered the most promising alternatives to lithium-ion batteries (LIBs) due to the abundant availability of sodium and their cost-effectiveness. Transition metal selenides (TMSes) are considered promising anodes for SIBs due to their economic efficiency and high theoretical capacity. Nevertheless, overcoming the challenges of sluggish reaction kinetics and severe structural damage is crucial to improving cycle life and rate capability. Herein, a simple microwave hydrothermal process was used to synthesize a nanocomposite of CoSe2 nanoparticles uniformly anchored on reduced graphene oxide nanosheets (CoSe2/rGO). The influences of rGO on the structure and electrochemical performance and Na+ diffusion kinetics are investigated through a series of characterization and electrochemical tests. The resulting CoSe2/rGO nanocomposite exhibits a remarkable initial specific capacity of 544 mAh g-1 at 0.5 A g-1, impressive rate capability (368 mAh g-1 at 20 A g-1), and excellent cycle life and maintains 348 mAh g-1 at 5 A g-1 over 1200 cycles. In addition, the in situ electrochemical impedance spectroscopy (EIS), ex situ X-ray diffraction (XRD), and transmission electron microscopy (TEM) tests are selected to further investigate the sodium storage mechanism.

Lactobacillus johnsonii Attenuates Liver Steatosis and Bile Acid Dysregulation in Parenteral Nutrition-Fed Rats.

Parenteral nutrition (PN), a vital therapy for patients with intestinal failure, can lead to the development of parenteral nutrition-associated liver disease (PNALD). In this study, we aimed to investigate the role of Lactobacillus johnsonii (L. johnsonii) in a rat model of PNALD. Total parenteral nutrition (TPN)-fed rats were used to assess the role of L. johnsonii in liver steatosis, bile acid metabolism, gut microbiota, and hepatocyte apoptosis. We observed a depletion of L. johnsonii that was negatively correlated with the accumulation of glycochenodeoxycholic acid (GCDCA), a known apoptosis inducer, in rats subjected to TPN. L. johnsonii attenuated TPN-induced liver steatosis by inhibiting fatty acid synthesis and promoting fatty acid oxidation. TPN resulted in a decrease in bile acid synthesis and biliary bile secretion, which were partially restored by L. johnsonii treatment. The gut microbial profile revealed depletion of pathogenic bacteria in L. johnsonii-treated rats. L. johnsonii treatment reduced both hepatic GCDCA levels and hepatocyte apoptosis compared with the TPN group. In vitro, L. johnsonii treatment inhibited GCDCA-induced hepatocyte apoptosis via its bile salt hydrolase (BSH) activity. Our findings suggest that L. johnsonii protects against liver steatosis, bile acid dysregulation, and hepatocyte apoptosis in TPN-fed rats.

A Magnesium Carbonate Hydroxide Nanofiber/Poly(Vinylidene Fluoride) Composite Membrane for High-Rate and High-Safety Lithium-Ion Batteries.

Simultaneously high-rate and high-safety lithium-ion batteries (LIBs) have long been the research focus in both academia and industry. In this study, a multifunctional composite membrane fabricated by incorporating poly(vinylidene fluoride) (PVDF) with magnesium carbonate hydroxide (MCH) nanofibers was reported for the first time. Compared to commercial polypropylene (PP) membranes and neat PVDF membranes, the composite membrane exhibits various excellent properties, including higher porosity (85.9%) and electrolyte wettability (539.8%), better ionic conductivity (1.4 mS·cm-1), and lower interfacial resistance (93.3 Ω). It can remain dimensionally stable up to 180 °C, preventing LIBs from fast internal short-circuiting at the beginning of a thermal runaway situation. When a coin cell assembled with this composite membrane was tested at a high temperature (100 °C), it showed superior charge-discharge performance across 100 cycles. Furthermore, this composite membrane demonstrated greatly improved flame retardancy compared with PP and PVDF membranes. We anticipate that this multifunctional membrane will be a promising separator candidate for next-generation LIBs and other energy storage devices, in order to meet rate and safety requirements.

Implication of the Autophagy-Related Protein Beclin1 in the Regulation of EcoHIV Replication and Inflammatory Responses.

The protein Beclin1 (BECN1, a mammalian homologue of ATG6 in yeast) plays an important role in the initiation and the normal process of autophagy in cells. Moreover, we and others have shown that Beclin1 plays an important role in viral replication and the innate immune signaling pathways. We previously used the cationic polymer polyethyleneimine (PEI) conjugated to mannose (Man) as a non-viral tool for the delivery of a small interfering (si) Beclin1-PEI-Man nanoplex, which specifically targets mannose receptor-expressing glia (microglia and astrocytes) in the brain when administered intranasally to conventional mice. To expand our previous reports, first we used C57BL/6J mice infected with EcoHIV and exposed them to combined antiretroviral therapy (cART). We show that EcoHIV enters the mouse brain, while intranasal delivery of the nanocomplex significantly reduces the secretion of HIV-induced inflammatory molecules and downregulates the expression of the transcription factor nuclear factor (NF)-kB. Since a spectrum of neurocognitive and motor problems can develop in people living with HIV (PLWH) despite suppressive antiretroviral therapy, we subsequently measured the role of Beclin1 in locomotor activities using EcoHIV-infected BECN1 knockout mice exposed to cART. Viral replication and cytokine secretion were reduced in the postmortem brains recovered from EcoHIV-infected Becn1+/- mice when compared to EcoHIV-infected Becn1+/+ mice, although the impairment in locomotor activities based on muscle strength were comparable. This further highlights the importance of Beclin1 in the regulation of HIV replication and in viral-induced cytokine secretion but not in HIV-induced locomotor impairments. Moreover, the cause of HIV-induced locomotor impairments remains speculative, as we show that this may not be entirely due to viral load and/or HIV-induced inflammatory cytokines.

Lycium RIN negatively modulate the biosynthesis of kukoamine A in hairy roots through decreasing thermospermine synthase expression.

Root bark (Lycii cortex) of Lycium contains high contents of characteristic bioactive compounds, including kukoamine A (KuA) and kukoamine B (KuB). RIPENING INHIBITOR (RIN) is well known as a master regulator of Solanaceaous fruit ripening. However, the role of RIN in the biosynthetic pathway of KuA in Lycium remains unclear. In this study, integrated transcriptomic, metabolomic analyses and hairy root system are used to characterize the role of RIN in KuA biosynthesis in Lycium. The ultra performance liquid chromatography electrospray ionization tandem mass spectrometry analysis revealed that KuA was significantly induced in LrRIN1 RNAi lines and not detected in overexpression lines. A total of 20,913 differentially expressed genes (DEGs) and 60 differentially accumulated metabolites (DAMs) were detected in LrRIN1 transgenic hairy roots, which were used for weighted gene co-expression network analysis. Our result reveals a high association between KuA and structural genes in the phenolamide pathway, which shows a negative correlation with LrRIN1. In addition, overexpression of the polyamine pathway gene thermospermine synthase LcTSPMS, a potential target gene of Lycium RIN, increased the contents of both KuA and KuB in L. chinense hairy root, indicating that TSPMS is responsible for KuA biosynthesis and is also the common upstream biosynthetic gene for both KuA and KuB. Our results lay a solid foundation for uncovering the biosynthetic pathway of KuA, which will facilitate the molecular breeding and genetic improvement of Lycium species.

Embedding Nano-Piezoelectrics into Heterointerfaces of S-Scheme Heterojunctions for Boosting Photocatalysis and Piezophotocatalysis.

Step-scheme (S-scheme) heterojunctions have exhibited great potential in photocatalysis due to their extraordinary light harvesting and high redox capacities. However, inadequate S-scheme recombination of useless carriers in weak redox abilities increases the probability of their recombination with useful ones in strong redox capabilities. Herein, a versatile protocol is demonstrated to overcome this impediment based on the insertion of nano-piezoelectrics into the heterointerfaces of S-scheme heterojunctions. Under light excitation, the piezoelectric inserter promotes interfacial charge transfer and produces additional photocarriers to recombine with useless electrons and holes, ensuring a more thorough separation of powerful ones for CO2 reduction and H2 O oxidation. When introducing extra ultrasonic vibration, a piezoelectric polarization field is established, which allows efficient separation of charges generated by the embedded piezoelectrics and expedites their recombination with weak carriers, further increasing the number of strong ones participating in the redox reactions. Encouraged by the greatly improved charge utilization, significantly enhanced photocatalytic and piezophotocatalytic activities in CH4 , CO, and O2 production are achieved by the designed stacked catalyst. This work highlights the importance in strengthening the necessary charge recombination in S-scheme heterojunctions and presents an efficient and novel strategy to synergize photocatalysis and piezocatalysis for renewable fuels and value-added chemicals production.

Decreased Expression of KLF4 Leading to Functional Deficit in Pediatric Patients with Intestinal Failure and Potential Therapeutic Strategy Using Decanoic Acid.

Pediatric intestinal failure (IF) is the reduction in gut function to below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth. The overall goal in treating IF is to achieve intestinal adaptation; however, the underlying mechanisms have not been fully understood. In this study, by performing single-cell RNA sequencing in pediatric IF patients, we found that decreased Kruppel-Like Factor 4 (KLF4) may serve as the hub gene responsible for the functional deficit in mature enterocytes in IF patients, leading to the downregulation of solute carrier (SLC) family transporters (e.g., SLC7A9) and, consequently, nutrient malabsorption. We also found that inducible KLF4 was highly sensitive to the loss of certain enteral nutrients: in a rodent model of total parenteral nutrition mimicking the deprivation of enteral nutrition, the expression of KLF4 dramatically decreased only at the tip of the villus and not at the bottom of crypts. By using IF patient-derived intestinal organoids and Caco-2 cells as in vitro models, we demonstrated that the supplementation of decanoic acid (DA) could significantly induce the expression of KLF4 along with SLC6A4 and SLC7A9, suggesting that DA may function as a potential therapeutic strategy to promote cell maturation and functional improvement. In summary, this study provides new insights into the mechanism of intestinal adaptation depending on KLF4, and proposed potential strategies for nutritional management using DA.

Prior memory encoding of negative distractors biases emotion-induced blindness.

Previous research has shown that the proactive deprioritization of emotional distractors through the provision of information about the distractors or passive habituation of emotional distractors may attenuate emotion-induced blindness (EIB) in the rapid serial visual presentation stream. However, whether prior memory encoding of emotional distractors could bias the EIB effect remains unknown. To address this question, this study employed a three-phase paradigm integrating an item-method direct forgetting (DF) procedure with a classic EIB procedure. Participants completed a memory coding phase to either remember or forget negative pictures, then performed an intermediate phase of the EIB test, and finally finished a recognition test. Critically, the same to-be-forgotten (TBF) and to-be-remembered (TBR) negative pictures in the memory learning phase were used as emotional distractors in the intermediate EIB test. The results replicated the typical DF effect by showing higher recognition accuracies for TBR pictures compared to those for TBF pictures. More importantly, the TBF negative distractors attenuated the EIB effect compared to the TBR negative distractors, but showed a comparable EIB effect as the novel negative distractors. These findings indicate that prior memory encoding manipulations of negative distractors could bias subsequent EIB effects, providing an important approach to modulate the EIB effect.

Extracellular Vesicles Released by Genetically Modified Macrophages Activate Autophagy and Produce Potent Neuroprotection in Mouse Model of Lysosomal Storage Disorder, Batten Disease.

Over the recent decades, the use of extracellular vesicles (EVs) has attracted considerable attention. Herein, we report the development of a novel EV-based drug delivery system for the transport of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1) to treat Batten disease (BD). Endogenous loading of macrophage-derived EVs was achieved through transfection of parent cells with TPP1-encoding pDNA. More than 20% ID/g was detected in the brain following a single intrathecal injection of EVs in a mouse model of BD, ceroid lipofuscinosis neuronal type 2 (CLN2) mice. Furthermore, the cumulative effect of EVs repetitive administrations in the brain was demonstrated. TPP1-loaded EVs (EV-TPP1) produced potent therapeutic effects, resulting in efficient elimination of lipofuscin aggregates in lysosomes, decreased inflammation, and improved neuronal survival in CLN2 mice. In terms of mechanism, EV-TPP1 treatments caused significant activation of the autophagy pathway, including altered expression of the autophagy-related proteins LC3 and P62, in the CLN2 mouse brain. We hypothesized that along with TPP1 delivery to the brain, EV-based formulations can enhance host cellular homeostasis, causing degradation of lipofuscin aggregates through the autophagy-lysosomal pathway. Overall, continued research into new and effective therapies for BD is crucial for improving the lives of those affected by this condition.