Explore the vast range of titles available.

Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.Recent advances in the development of gene therapy tools provide hope that these approaches might modulate the altered gene expression that characterizes many CNS disorders. Gao et al. provide an overview of current gene therapy strategies, highlighting the interdependence of therapeutic modality, delivery vehicle and administration route for translational success.

Development of novel therapies for central nervous system (CNS) disorders has experienced a high failure rate in clinical trials owing to unsatisfactory efficacy and adverse effects. One of the major reasons for limited therapeutic efficacy is the poor penetration of drugs across the blood–brain barrier. Despite the development of multiple drug delivery platforms, the overall drug accumulation in the brain remains sub-optimal. Another critical but overlooked factor is achieving precision delivery to a specific region and cell type in the brain. This specificity is crucial because most neurological disorders exhibit region-specific vulnerabilities. Multiple trials have failed owing to adverse CNS effects induced by nonspecific drug targeting. In this Review, we highlight the key regions and cell types that should be targeted in different CNS diseases. We discuss how physiological barriers and disease-mediated changes in the blood–brain barrier and the overall brain can impact the precision delivery of therapeutics via the systemic route. We then perform a systematic analysis of the current state-of-the-art approaches developed to overcome these barriers and achieve precision targeting at different levels. Finally, we discuss potential approaches to accelerate the development of precision delivery systems and outline the challenges and future research directions. The development of therapeutics for central nervous system disorders suffers from high failure rates owing to poor blood–brain barrier penetration and lack of targeted delivery. This Review discusses how nanoparticles can help to overcome these challenges to enable precision targeting of the brain for different central nervous system diseases.

This study investigates the relationship between soundscape perception and pro-environmental behaviors within the Grand Canal National Cultural Park. The research was conducted across four parks in China’s Tongzhou Canal National Cultural Tourism Zone, employing field measurements, questionnaires, and audio-visual experiments. Four distinct soundscape types were identified: natural soundscapes, artificial soundscapes, mechanical soundscapes, and canal cultural soundscapes. Expert-led structural equation modeling (SEM) was utilized to examine correlations between soundscape perception and protective behaviors, with the objective of enhancing soundscape quality to promote public protective behaviors toward the Grand Canal National Cultural Park.The results reveal significant findings: Natural and canal cultural soundscapes positively influence both environmentally responsible behaviors and heritage conservation behaviors. Artificial soundscapes demonstrate a positive impact exclusively on heritage conservation behaviors, while mechanical soundscapes exhibit no significant effect on either protective behavior. Furthermore, place attachment mediates the relationship between soundscape perception and pro-environmental behaviors, strengthening their connection.Based on these findings and integrated with soundscape ecology theory, a tripartite model linking soundscape perception, place attachment, and protective behaviors was constructed. This research advances the multidisciplinary field of multisensory landscapes by providing empirical evidence for soundscape-behavior interactions. It underscores the critical need to incorporate soundscape considerations in canal park planning to foster sustainable environmental stewardship.

As research on national cultural parks advances, the significance of conducting multi-dimensional perception evaluations of their cultural ecosystem services (CESs) becomes increasingly apparent. This study examines the eight dimensions of CESs within the Grand Canal National Cultural Park from the perspective of soundscape preference. Using Tongzhou Grand Canal Forest Park as a case study, five categories of soundscapes comprising 19 sound sources were identified through the analysis of online textual data. This study then collected public preferences and perceptions of these five soundscapes via on-site questionnaires and analyzed the data using SPSS26 for correlation and IPA analyses. The results indicate that the overall evaluation of the park’s CESs is positive. There is a significant mutual influence between soundscape preference and CES perception. Specifically, the preference for natural soundscape significantly impacts the evaluation of each CES dimension, while satisfaction with leisure and entertainment is positively correlated with preferences for all types of soundscapes. Additionally, there are notable differences in soundscape preference among different age groups. These findings not only enhance our understanding of soundscape planning in national cultural parks but also provide valuable guidance for their management and design.

Alzheimer’s disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood 1 – 3 . Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer’s disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer’s disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer’s disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer’s disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology. A regional atlas of the ageing human brain—spanning six distinct anatomical regions from individuals with and without Alzheimer’s dementia—provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology

In pancreatic ductal adenocarcinoma (PDAC), tumour associated macrophages (TAMs) are a heterogeneous immune cell population that interact with cancer cells to promote malignancy, chemo-resistance, and immunosuppression. Aside from TAMs, hypoxia is a prominent feature of PDAC that can rewire cells to survive and enhance malignancy in the tumour microenvironment (TME). Deciphering the interactions between macrophages, cancer cells and hypoxia could lead to the development of effective immune-targeted therapies for PDAC. However, there are only a few models that physiologically recapitulate the PDAC TME and allow for meaningful interrogation of cancer-immune cell interactions in hypoxia. Here, we develop a model of primary macrophages and PDAC patient organoid-derived cells by adapting TRACER, a paper-based, engineered 3D model that allows snapshot analysis of cellular response in hypoxia. In this study, we establish a direct co-culture method of primary macrophages and PDAC organoid cells in TRACER and demonstrate that TRACER co-cultures generate hypoxic gradients and show expected phenotypic responses to this hypoxic gradient. Moreover, we report for the first time in a human in vitro model that hypoxic macrophages exert a graded chemoprotective effect on gemcitabine-treated PDAC organoid cells, and that interactions between cancer cells and macrophages from the inner layers of TRACER indirectly attenuate the inflammatory response of donor-derived T-cells. Overall, the TRACER co-culture system is a novel, fully human 3D in vitro cancer-immune model for evaluating the response of macrophages and cancer cells in a hypoxic gradient.

Drought adversely affects crop growth and yields. The cloning and characterization of drought- or abscisic acid (ABA)-inducible promoters is of great significance for their utilization in the genetic improvement of crop resistance. Our previous studies have shown that maize sulfite oxidase (SO) has a sulfite-oxidizing function and is involved in the drought stress response. However, the promoter of the maize SO gene has not yet been characterized. In this study, the promoter (ZmSOPro, 1194 bp upstream region of the translation initiation site) was isolated from the maize genome. The in-silico analysis of the ZmSOPro promoter identified several cis-elements responsive to the phytohormone ABA and drought stress such as ABA-responsive element (ABRE) and MYB binding site (MBS), besides a number of core cis-acting elements, such as TATA-box and CAAT-box. A 5′ RACE (rapid amplification of cDNA ends) assay identified an adenine residue as the transcription start site of the ZmSO. The ZmSOPro activity was detected by β-glucuronidase (GUS) staining at nearly all developmental stages and in most plant organs, except for the roots in transgenic Arabidopsis. Moreover, its activity was significantly induced by ABA and drought stress. The 5′-deletion mutant analysis of the ZmSOPro in tobacco plants revealed that a 119-bp fragment in the ZmSOPro (upstream of the transcription start site) is a minimal region, which is required for its high-level expression. Moreover, the minimal ZmSOPro was significantly activated by ABA or drought stress in transgenic plants. Further mutant analysis indicated that the MBS element in the minimal ZmSOPro region (119 bp upstream of the transcription start site) is responsible for ABA and drought-stress induced expression. These results improve our understanding of the transcriptional regulation mechanism of the ZmSO gene, and the characterized 119-bp promoter fragment could be an ideal candidate for drought-tolerant gene engineering in both monocot and dicot crops.

Microglial activation-induced neuroinflammation and impaired neuronal mitophagy are recognized as pivotal pathogeneses in Parkinson’s disease (PD). However, the role of microglial mitophagy in microglial activation during PD development remains unclear, and therapeutic interventions targeting this interaction are lacking. Rhapontigenin (Rhap), a stilbenoid enriched in Vitis vinifera , exhibits dual anti-neuroinflammatory and mitophagy-enhancing properties, but its therapeutic potential and mechanisms in PD are unexplored. This study aimed to investigate the therapeutic efficacy of Rhap on neurodegeneration in a PD model and explore its underlying mechanism. Here, we showed that Rhap administration significantly ameliorated motor deficits, dopaminergic neuron loss, and neuroinflammation in MPTP-induced PD mice. Mechanistically, Rhap suppressed neuroinflammation by inhibiting the cGAS-STING-NF-κB signaling axis in both PD model mice and MPP⁺-induced BV2 microglia. Crucially, its anti-inflammatory effects depend on the PINK1-mediated enhancement of microglial mitophagy to control cytosolic mtDNA leakage. Specifically, Rhap bound to PINK1 strengthened the PINK1-DRP1 interaction, promoted mitochondrial fission in damaged organelles, and enhanced mitophagy clearance. This mitophagy activation prevents cytosolic leakage of mitochondrial DNA (mtDNA), thereby attenuating mtDNA-cGAS-STING-NF-κB-derived neuroinflammation and subsequent neurodegeneration in PD. PINK1 deficiency in BV2 microglia abolished Rhap’s ability to suppress mtDNA-cGAS-STING-NF-κB activation and enhance mitophagy. Overall, our study reveals a previously unrecognized mechanism by which Rhap ameliorates PD-associated neurodegeneration through dual modulation of PINK1/DRP1-dependent microglial mitophagy and the mtDNA-cGAS-STING-NF-κB neuroinflammatory axis, suggesting a potential therapeutic strategy for PD and related neurodegenerative disorders.

With the advancement of technology and the development of society, live-streamed teaching, characterized by real-time interaction between teachers and students, has emerged as a new form of online education and has rapidly evolved in practice. However, in online live-streamed teaching, there are still various issues, such as insufficient teacher–student interaction and interactive functionalities, that fail to meet learners’ needs. These issues impact the efficiency and user experience of online live-streamed teaching. Currently, scholars mostly examine these issues from the perspective of online teaching system design, paying less attention to exploring the interactive mechanisms from the point of view of user perception. Within the context of Chinese education, based on the technology acceptance model, this study investigated student personality traits, interactive motivations, and platform interactive functionalities, and the aim of this study was to explore the influencing factors and mechanisms of online live-streamed teaching interactions. A total of 281 university students participated in the survey, and the results indicated that the platform’s interactive functionalities significantly and positively predicted perceived usability and perceived ease of use. Moreover, the students’ personality traits significantly and positively predicted interaction motivations and usage attitudes. Furthermore, usage attitudes significantly and positively predicted interactive behavior. A mediation analysis revealed that perceived usability and perceived ease of use mediated the relationship between the platform’s interactive functionalities and usage attitudes. Additionally, interaction motivations mediated the relationship between the students’ personality traits and interactive behavior. We discuss the potential implications and practical significance of the current research findings. The results of this study offer viable strategies for enhancing current online educational practices, aiding educational designers in order to better organize and promote online educational interactions to elevate student engagement and advance the sustainable development of digital education.