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This study establishes quantitative relationships between neighborhood layouts, as evaluated by key neighborhood morphological parameters and pedestrian wind environments across China’s five major climate zones. We analyzed 3204 residential neighborhoods using satellite imaging and simulated 281 scenarios by CFD simulations, identifying six typical neighborhood layouts and quantifying their performance in terms of climate specific wind comfort criteria. This work takes an approach that takes into account mechanical wind effects and region-specific criteria for evaluating pedestrian-level wind environment performance, going beyond previous studies that utilize universal evaluation standards. The most influential parameter is building enclosure ratio with sensitivity indices of 0.844 for winter wind proofing. Closed perimeter layout confers 15–20% better winter wind proofing in cold climates and semi-open design enhances summer ventilation by 12–18% in hot climates according to our cross-climate analysis. Quantitative optimization adopting regression technique (R2 = 0.727–0.810) points to an optimal enclosure ratio of 0.25–0.28 or 0.52–0.61 with aspect ratio of 1.75–2.75. The results can provide evidence-based design guidelines for high-rise residential neighborhood planning and pedestrian wind environment, aiming to improve urban livability and support climate adaptation strategies across a broad range of climate zones.

Background Parkinson’s disease (PD) is the most prevalent neurodegenerative disorder that is characterised by selective loss of midbrain dopaminergic (DA) neurons. Chronic inflammation of the central nervous system is mediated by microglial cells and plays a critical role in the pathological progression of PD. Brain-specific microRNA-124 (miR-124) expression is significantly downregulated in lipopolysaccharide (LPS)-treated BV2 cells and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. However, whether abnormal miR-124 expression could regulate the activation of microglia remains poorly understood. Methods BV2 cells were activated by exposure to LPS, and the expression levels of miR-124, mitogen-activated protein kinase kinase kinase 3 (MEKK3), and the nuclear factor of kappaB (NF-κB) p-p65 were analysed. Over-expression and knockdown studies of miR-124 were performed to observe the effects on MEKK3/NF-κB signalling pathways, and the induction of pro-inflammatory and neurotoxic factors was assessed. In addition, a luciferase reporter assay was conducted to confirm whether MEKK3 is a direct target of miR-124. Meanwhile, production of miR-124, MEKK3, and p-p65; midbrain DA neuronal death; or activation of microglia were analysed when treated with or without miR-124 in the MPTP-induced model of PD. Results We found that the knockdown of MEKK3 could inhibit the activation of microglia by regulating NF-κB expression. Over-expression of miR-124 could effectively attenuate the LPS-induced expression of pro-inflammatory cytokines and promote the secretion of neuroprotective factors. We also first identified a unique role of miR-124 in mediating the microglial inflammatory response by targeting MEKK3/NF-κB signalling pathways. In the microglial culture supernatant (MCS) transfer model, over-expression of the miR-124 or knockdown of MEKK3 in BV2 cells prevented SH-SY5Y from apoptosis and death. Moreover, MEKK3 and p-p65 were abundantly expressed in the midbrain. Furthermore, their expression levels increased and microglial activation was observed in the MPTP-induced model of PD. In addition, exogenous delivery of miR-124 could suppress MEKK3 and p-p65 expression and attenuate the activation of microglia in the substantia nigra pars compacta of MPTP-treated mice. miR-124 also could prevent MPTP-dependent apoptotic midbrain DA cell death in a MPTP-induced PD model. Conclusions Taken together, our data suggest that miR-124 can inhibit neuroinflammation in the development of PD by regulating the MEKK3/NF-κB signalling pathways and implicate miR-124 as a potential therapeutic target for regulating the inflammatory response in PD.

The intracellular aggregation of α-synuclein in neurons/glias is considered to be a key step in the pathogenesis of synucleinopathy (including PD, DLB, MSA, etc.). Increasing evidence indicates that the initial pathological α-synuclein aggregates can replicate themselves and propagate in a “seeding” manner to multiple areas of the brain and even to peripheral skin tissue, which makes it the most important biomarker for the diagnosis of synucleinopathies in recent years. The amplification and propagation capabilities of α-synuclein aggregates are very similar to those of prion-like diseases, which are based on the inherent self-recruitment capabilities of existing misfolded proteins. In vitro, by adding a small amount of pre-formed fibrils to the monomer solution, the recruitment process can be reproduced in a simplified model which may, to a certain extent, reveal part of the properties of α-synuclein aggregates. In this study, we explored the elongation rate of α-synuclein seeds under a quiescently incubating condition (rather than shaking/agitating). By using ThT fluorescence assay, we compared and quantified the elongation fluorescence curves to explore the factors that affect fibril elongation. These factors include proteins concentration, temperature, NaCl strength, SDS, temperature pretreatment and so on. Our work further describes the elongation of α-synuclein fibrils under quiescent incubation conditions. This may have important implications for the in vitro amplification and preservation of α-synuclein aggregates to further understand the prion-like transmission mechanism of PD.

Autophagy dysfunction has been directly linked with the onset and progression of Parkinson’s disease (PD), but the underlying mechanisms are not well understood. High-mobility group A1 (HMGA1), well-known chromatin remodeling proteins, play pivotal roles in diverse biological processes and diseases. Their function in neural cell death in PD, however, have not yet been fully elucidated. Here, we report that HMGA1 is highly induced during dopaminergic cell death in vitro and mice models of PD in vivo . Functional studies using genetic knockdown of endogenous HMGA1 show that HMGA1 signaling inhibition accelerates neural cell death, at least partially through aggravating MPP + -induced autophagic flux reduction resulting from partial block in autophagic flux at the terminal stages, indicating a novel potential neuroprotective role for HMGA1 in dopaminergic neurons death. MicroRNA-103/107 (miR-103/107) family, which is highly expressed in neuron, coordinately ensures proper end-stage autophagy. We further illustrate that MPP + /1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced HMGA1 elevation counterparts the effect of miR-103/107 downregulation by directly binding to their promoters, respectively, sustaining their expression in MPP + -damaged MN9D cells and modulates autophagy through CDK5R1/CDK5 signaling pathway. We also find that HMGA1 is a direct target of miR-103/107 family. Thus, our results suggest that HMGA1 forms a negative feedback loop with miR-103/107-CDK5R1/CDK5 signaling to regulate the MPP + /MPTP-induced autophagy impairment and neural cell death. Collectively, we identify a paradigm for compensatory neuroprotective HMGA1 signaling in dopaminergic neurons that could have important therapeutic implications for PD.

Background Alzheimer’s disease (AD) has a significant impact on an individual’s health and places a heavy burden on society. Studies have emphasized the importance of microglia in the progression and development of AD. Interferon responses and Interferon-stimulated genes (ISGs) significantly function in neuroinflammatory and neurodegenerative diseases involving AD. Therefore, further exploration of the relationship among microglia, ISGs, and neuroinflammation in AD is warranted. Methods Microglia datasets from the GEO database were retrieved, along with additional microglia RNA-seq data from laboratory mice. Weighted Correlation Network Analysis was used on the training dataset to identify gene co-expression networks. Genes from the black module were intersected with interferon-stimulated genes, and differentially expressed genes (DEGs) were identified. Machine learning algorithms were applied to DEGs, and genes selected by both methods were identified as hub genes, with ROC curves used to evaluate their diagnostic accuracy. Gene Set Enrichment Analysis was performed to reveal functional pathways closely relating to hub genes. Microglia cells were transfected with siRNAs targeting Oas1g and STAT1. Total RNA from microglia cells and mouse brain tissues was extracted, reverse-transcribed, and analyzed via qRT-PCR. Proteins were extracted from cells, quantified, separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies. Microglia cells were fixed, permeabilized, blocked, and stained with antibodies for STAT1, then visualized and photographed. Results Bioinformatics and machine learning algorithms revealed that Oas1g was identified as a hub gene, with an AUC of 0.812. Enrichment Analysis revealed that Oas1g is closely associated with interferon-related pathways. Expression of Oas1g was validated in AD mouse models, where it was significantly upregulated after microglial activation. Knockdown experiments suggested siOas1g attenuated the effect of siSTAT1, and the expressions of STAT1 and p-STAT1 were elevated. siOas1g could reverse the effect of siSTAT1, indicating that Oas1g potentially regulates the ISGs through the STAT1 pathway. Conclusion We demonstrated that Oas1g was identified as a hub ISG in AD and can downregulate the activation of IFN-β and STAT1, reducing the expression of ISGs in neuroinflammation. Oas1g might potentially be a beneficial candidate for both prevention and treatment of AD.

Purpose Cisplatin is a widely used and effective chemotherapeutic agent for most solid malignant tumors. However, cisplatin-induced ototoxicity is a common adverse effect that limits the therapeutic efficacy of tumors in the clinic. To date, the specific mechanism of ototoxicity has not been fully elucidated, and the management of cisplatin-induced ototoxicity is also an urgent challenge. Recently, some authors believed that miR34a and mitophagy played a role in age-related and drug-induced hearing loss. Our study aimed to explore the involvement of miR-34a/DRP-1-mediated mitophagy in cisplatin-induced ototoxicity. Methods In this study, C57BL/6 mice and HEI-OC1 cells were treated with cisplatin. MiR-34a and DRP-1 levels were analyzed by qRT‒PCR and western blotting, and mitochondrial function was assessed via oxidative stress, JC-1 and ATP content. Subsequently, we detected DRP-1 levels and observed mitochondrial function by modulating miR-34a expression in HEI-OC1 cells to determine the effect of miR-34a on DRP-1-mediated mitophagy. Results MiR-34a expression increased and DRP-1 levels decreased in C57BL/6 mice and HEI-OC1 cells treated with cisplatin, and mitochondrial dysfunction was involved in this process. Furthermore, the miR-34a mimic decreased DRP-1 expression, enhanced cisplatin-induced ototoxicity and aggravated mitochondrial dysfunction. We further verified that the miR-34a inhibitor increased DRP-1 expression, partially protected against cisplatin-induced ototoxicity and improved mitochondrial function. Conclusion MiR-34a/DRP-1-mediated mitophagy was related to cisplatin-induced ototoxicity and might be a novel target for investigating the treatment and protection of cisplatin-induced ototoxicity.

Cisplatin-induced ototoxicity is one of the major adverse effects in cisplatin chemotherapy, and hearing protective approaches are unavailable in clinical practice. Recent work unveiled a critical role of autophagy in cell survival in various types of hearing loss. Since the excessive activation of autophagy can contribute to apoptotic cell death, whether the activation of autophagy increases or decreases the rate of cell death in CDDP ototoxicity is still being debated. In this study, we showed that CDDP induced activation of autophagy in the auditory cell HEI-OC1 at the early stage. We then used rapamycin, an autophagy activator, to increase the autophagy activity, and found that the cell death significantly decreased after CDDP injury. In contrast, treatment with the autophagy inhibitor 3-methyladenine (3-MA) significantly increased cell death. In accordance with results, rapamycin alleviated CDDP-induced death of hair cells in zebrafish lateral line and cochlear hair cells in mice. Notably, we found that CDDP-induced increase of Sirtuin 1 (SIRT1) in the HEI-OC1 cells modulated the autophagy function. The specific SIRT1 activator SRT1720 could successfully protect against CDDP-induced cell loss in HEI-OC1 cells, zebrafish lateral line, and mice cochlea. These findings suggest that SIRT1 and autophagy activation can be suggested as potential therapeutic strategies for the treatment of CDDP-induced ototoxicity.

BackgroundParkinson's disease (PD) is a common degenerative nervous system disease. At present, there are certain limitations in various treatment options aimed at preventing or delaying the progression of PD. Therefore, the exploration of new drugs for PD is beneficial. Mendelian randomization (MR) analysis can be used to explore the association between drugs and diseases. In this study, MR analysis was adopted to investigate the causal relationship between 23 drugs and PD. These drugs have been approved for the treatment of different diseases, such as salicylic acid and derivatives (collectively called salicylates, e.g., aspirin, used for fever and pain relief), antithrombotic agents (e.g., warfarin, aspirin, used for preventing thrombotic events).MethodsThe GWAS data for the 23 drugs were obtained from the UK Biobank (UKB) project, while the GWAS data for PD were sourced from FinnGen. Single-Nucleotide Polymorphisms (SNPs) were selected as instrumental variables (IVs). We first performed a series of quality control steps (including MR-PRESSO) to select the appropriate SNPs. Two-sample MR analysis was performed using five different methods, including inverse variance weighting (IVW) with random-effects model, weighted median, MR-Egger, simple model, and weighted model. At the same time, sensitivity analysis was carried out using the MR-Egger and Cochran's Q test to ensure the authenticity and reliability of the results.ResultsIn MR-PRESSO, salicylates and antithrombotic agents showed statistically significant associations with PD, respectively. In the main MR analysis (IVW), there was a negative causal relationship between salicylates and PD (OR = 0.73, 95% CI = 0.54–0.98, p = .039). Similarly, there was a negative causal relationship between antithrombotic agents and PD (OR = 0.70, 95%CI = 0.52–0.96, p = .027). No statistically significant association was found between the remaining 21 drugs and PD.ConclusionThis MR study demonstrated that salicylates and antithrombotic agents can reduce the risk of PD, thus providing a novel avenue for future drug exploration in PD.

Cystathionine γ-lyase (CSE) is the second enzyme in the trans-sulfuration pathway that converts cystathionine to cysteine. It is also one of three major enzymes responsible for the biosynthesis of hydrogen sulfide (H2S). CSE is believed to be the major source of endogenous H2S in the cardiovascular system, and the CSE/H2S system plays a crucial role in a variety of physiological and pathological processes. However, the regulatory mechanism of the CSE/H2S system is less well understood, especially at the post-translational level. Here, we demonstrated that the persulfidation of CSE inhibits its activity by ~2-fold in vitro. The loss of this post-translational modification in the presence of dithiothreitol (DTT) results in a reversal of basal activity. Cys137 was identified as the site for persulfidation by combining mass spectrometry, mutagenesis, activity analysis and streptavidin–biotin pull-down assays. To test the physiological relevance of the persulfidation regulation of CSE, human aortic vascular smooth muscle cells (HA-VSMCs) were incubated with vascular endothelial growth factor (VEGF), which is known to enhance endogenous H2S levels. Under these conditions, consistent with the change tendency of the cellular H2S level, the CSE persulfidation levels increased transiently and then gradually decreased to the basal level. Collectively, our study revealed a negative feedback regulation mechanism of the CSE/H2S system via the persulfidation of CSE and demonstrated the potential for maintaining cellular H2S homeostasis under oxidative stress conditions, particularly in tissues where CSE is a major source of H2S.

In December 2019, a new type of coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appeared in Wuhan, China. Serious outbreaks of coronavirus disease 2019 (COVID-19), related to the SARS-CoV-2 virus, have occurred throughout China and the world. Therefore, we intend to shed light on its potential clinical and epidemiological characteristics. In this retrospective study, we included 50 confirmed fatal cases of SARS-CoV-2 reported on Chinese official media networks from January 16, 2020, to February 5, 2020. All the cases were confirmed by local qualified medical and health institutions. Specific information has been released through official channels. According to the contents of the reports, we recorded in detail the gender, age, first symptom date, death date, primary symptoms, chronic fundamental diseases, and other data of the patients, and carried out analyses and discussion. In total, 50 fatal cases were reported: median age was 70 y old, and males were 2.33 times more likely to die than females. The median number of days from the first symptom to death was 13, and that length of time tended to be shorter among people aged 65 and older compared with those younger than 65 (12 days vs 17 days; P = 0.046). Therefore, the older patients had fewer number of days from the first symptom to death (r = -0.40; P = 0.012). In our study, we found that most of the deaths were elderly men with chronic fundamental diseases, and their COVID-19 progression to death time was shorter. At the same time, we demonstrated that older men are more likely to become infected with COVID-19, and the risk of death is positively correlated with age.