Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune neurologic disorder, the genetic etiology of which remains poorly understood. Our study aims to investigate the genetic basis of this disease in the Chinese Han population. METHODS: We performed a genome-wide association study and fine-mapping study within the major histocompatibility complex (MHC) region of 413 Chinese patients with anti-NMDAR encephalitis recruited from 6 large tertiary hospitals and 7,127 healthy controls. RESULTS: Our genome-wide association analysis identified a strong association at the IFIH1 locus on chromosome 2q24.2 (rs3747517, p = 1.06 × 10-8, OR = 1.55, 95% CI, 1.34-1.80), outside of the human leukocyte antigen (HLA) region. Furthermore, through a fine-mapping study of the MHC region, we discovered associations for 3 specific HLA class I and II alleles. Notably, HLA-DQB1*05:02 (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59) demonstrates the strongest association among classical HLA alleles, closely followed by HLA-A*11:01 (p = 4.36 × 10-7; OR, 1.52; 95% CI 1.29-1.79) and HLA-A*02:07 (p = 1.28 × 10-8; OR, 1.87; 95% CI 1.50-2.31). In addition, we uncovered 2 main HLA amino acid variation associated with anti-NMDAR encephalitis including HLA-DQß1-126H (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59), exhibiting a predisposing effect, and HLA-B-97R (p = 3.40 × 10-8; OR, 0.63; 95% CI 0.53-0.74), conferring a protective effect. Computational docking analysis suggested a close relationship between the NR1 subunit of NMDAR and DQB1*05:02. DISCUSSION: Our findings indicate that genetic variation in IFIH1, involved in the type I interferon signaling pathway and innate immunity, along with variations in the HLA class I and class II genes, has substantial implications for the susceptibility to anti-NMDAR encephalitis in the Chinese Han population.

Synergistic Radiation Effects in PPD CMOS Image Sensors Induced by Neutron Displacement Damage and Gamma Ionization Damage.

The synergistic effects on the 0.18 µm PPD CISs induced by neutron displacement damage and gamma ionization damage are investigated. The typical characterizations of the CISs induced by the neutron displacement damage and gamma ionization damage are presented separately. The CISs are irradiated by reactor neutron beams up to 1 × 1011 n/cm2 (1 MeV neutron equivalent fluence) and 60Co γ-rays up to the total ionizing dose level of 200 krad(Si) with different sequential order. The experimental results show that the mean dark signal increase in the CISs induced by reactor neutron radiation has not been influenced by previous 60Co γ-ray radiation. However, the mean dark signal increase in the CISs induced by 60Co γ-ray radiation has been remarkably influenced by previous reactor neutron radiation. The synergistic effects on the PPD CISs are discussed by combining the experimental results and the TCAD simulation results of radiation damage.

Application of 3D visualization technology based on hematoma edge key points setting for emergency hypertensive cerebral hemorrhage surgery in primary hospitals.

OBJECTIVE: This study aims to explore the application potential of 3D visualization technology based in emergency hypertensive cerebral hemorrhage surgery in primary hospitals. The specific goal is to use 3DSlicer software to perform 3D reconstruction and body surface projection on patients with hypertensive cerebral hemorrhage, provide accurate hematoma location information, help surgeons determine the specific location of hematoma on the body surface, and reduce the expansion of surgical incisions. METHODS: 3D reconstruction technology based on 3DSlicer software was employed to process CT images of patients with cerebral hemorrhage. By segmenting and reconstructing the images, a 3D model of the hematoma was generated and projected onto the patient's body surface. Utilizing the functionalities of 3DSlicer software in conjunction with the surgeon's anatomical knowledge, accurate hematoma positioning on the body surface was achieved. RESULTS: 23 patients were enrolled in this study, and underwent successful surgical evacuation. The implementation of 3D visualization technology using 3DSlicer software is expected to provide precise hematoma localization information for emergency hypertensive intracerebral hemorrhage surgery in primary hospitals. This approach will enable surgeons to accurately determine the appropriate surgical incision, thereby minimizing unnecessary trauma and improving the overall success rate of surgery. CONCLUSION: This study demonstrates the potential application of 3D visualization technology based on 3DSlicer software in emergency hypertensive cerebral hemorrhage surgery within primary hospitals. By utilizing 3DSlicer software for hematoma localization, accurate information support can be provided to assist surgeons in managing patients with hypertensive cerebral hemorrhage.

Assessment of vertical cooling performance of trees over different surface covers.

Tree-induced cooling benefits are associated with various factors, such as canopy morphology, surface cover, and environmental configuration. However, limited studies have analyzed the sensitivity of tree-induced cooling effects to the combination of such factors. Most studies have focused on 1.5-m cooling performance, and few studies on the variability of the under-tree vertical cooling performance. Therefore, this study aims to investigate the vertical cooling performance of different combinations of trees and surface covers. The study was completed in Chongqing, China, with field experiments capturing vertical air temperature and wind speed at 0.5, 1.0, 1.5, 2.0 and 2.5 m under two typical combinations of "tree + grass" (ComA) and "tree + shrubs" (ComB), and capturing 1.5 m microclimatic environments of a control group with hard pavement without tree shade (REF). The results show that at an average ambient temperature of 33 °C, the maximum air-cooling temperatures for ComA and ComB were 2.46 °C and 1.78 °C, respectively. An increase in the ambient temperature corresponded to a decrease in the cooling effect difference between ComA and ComB. ComA had a maximum vertical temperature difference of 1.01 °C between H1.5m and H2.0m. Between H2.5m and H2.0m, the maximum vertical temperature difference for ComB was 1.64 °C. This study explored the changing patterns of under-tree vertical temperatures under different tree and surface cover combinations, conducive to clarifying the key elements affecting tree cooling performance. The results have implications for accurate thermal comfort assessments and provide a theoretical basis for fine-tuning the design of under-tree spaces.

Inhibition of TGF-ß1-induced epithelial-mesenchymal transition in gliomas by DMC-HA.

DMC-HA, a novel HDAC inhibitor, has previously demonstrated antiproliferative activity against various cancers, including gliomas. However, the role of DMC-HA in the regulation of EMT and its underlying mechanisms remain unknown. This study aimed to explore the effects of DMC-HA on TGF-ß1-induced EMT in human gliomas and the underlying mechanisms involved. Our results showed that TGF-ß1 induced EMT of U87 and U251 cells, leading to a decrease in epithelial marker ZO-1 and an increase in mesenchymal markers N-cadherin and Vimentin. Moreover, TGF-ß1 treatment resulted in a significant increase in the migratory and invasive abilities of the cells. However, treatment with DMC-HA effectively inhibited the augmented migration and invasion of glioma cells induced by TGF-ß1. Additionally, DMC-HA inhibits TGF-ß1-induced EMT by suppressing canonical Smad pathway and non-canonical TGF-ß/Akt and Erk signalling pathways. These findings suggest that DMC-HA has potential therapeutic implications for gliomas by inhibiting EMT progression.

Public responses to urban heat and payment for heat-resilient infrastructure: implications for heat action plan formulation.

Heat action plans should be urgently formulated to enable urban managers, planners, and designers to take appropriate actions for mitigation and adaptation. However, few studies have been conducted to investigate the societal needs and knowledge gaps regarding heat mitigation and adaptation. To address such research gaps, this paper presents an empirical study of 574 questionnaires in Chengdu, China, to explore heat-related impacts, public responses, and driving mechanisms. The results indicated that outdoor activities and work/study were more sensitive to extreme heat than transportation, sleep/rest, and diet. Heat-related impacts on physiological health were at the same level as those on psychological health, where digestive system illness and emotional irritability were the most prevalent physiological and psychological symptoms. Respondents' knowledge of heat-related threats, adaptation awareness, and adaptation knowledge were insufficient, compared with heat severity. The payment willingness among the respondents was not strong and payment amount was not high. Poorer, healthier, and the less affected in outdoor activities were positive groups in payment willingness, while the group which experienced heat-related impacts on outdoor activities could pay more compared with other groups. Overall, these results help to shape the main contents of heat action plans.

Roles of microRNA-124 in traumatic brain injury: a comprehensive review.

Traumatic brain injury (TBI) is a prominent global cause of mortality due to the limited availability of effective prevention and treatment strategies for this disorder. An effective molecular biomarker may contribute to determining the prognosis and promoting the therapeutic efficiency of TBI. MicroRNA-124 (miR-124) is most abundantly expressed in the brain and exerts different biological effects in a variety of diseases by regulating pathological processes of apoptosis and proliferation. Recently, increasing evidence has demonstrated the association between miR-124 and TBI, but there is still a lack of relevant literature to summarize the current evidence on this topic. Based on this review, we found that miR-124 was involved as a regulatory factor in cell apoptosis and proliferation, and was also strongly related with the pathophysiological development of TBI. MiR-124 played an essential role in TBI by interacting with multiple biomolecules and signaling pathways, such as JNK, VAMP-3, Rela/ApoE, PDE4B/mTOR, MDK/TLR4/NF-κB, DAPK1/NR2B, JAK/STAT3, PI3K/AKT, Ras/MEK/Erk. The potential benefits of upregulating miR-124 in facilitating TBI recovery have been identified. The advancement of miRNA nanocarrier system technology presents an opportunity for miR-124 to emerge as a novel therapeutic target for TBI. However, the specific mechanisms underlying the role of miR-124 in TBI necessitate further investigation. Additionally, comprehensive large-scale studies are required to evaluate the clinical significance of miR-124 as a therapeutic target for TBI.

Agomir-331 Suppresses Reactive Gliosis and Neuroinflammation after Traumatic Brain Injury.

Traumatic brain injury usually triggers glial scar formation, neuroinflammation, and neurodegeneration. However, the molecular mechanisms underlying these pathological features are largely unknown. Using a mouse model of hippocampal stab injury (HSI), we observed that miR-331, a brain-enriched microRNA, was significantly downregulated in the early stage (0-7 days) of HSI. Intranasal administration of agomir-331, an upgraded product of miR-331 mimics, suppressed reactive gliosis and neuronal apoptosis and improved cognitive function in HSI mice. Finally, we identified IL-1ß as a direct downstream target of miR-331, and agomir-331 treatment significantly reduced IL-1ß levels in the hippocampus after acute injury. Our findings highlight, for the first time, agomir-331 as a pivotal neuroprotective agent for early rehabilitation of HSI.

Exploring the potential of roof greening for low-carbon landscapes.

As one type of urban artificial ecosystems, roof greening exhibits carbon source/sink characteristics during their life cycle. The carbon cycle mechanism is complex. The lack of exhaustive carbon performance quantification methods and assessment indicators hinders the promotion and implementation of green roof urban decarboni-zation. Focusing on the quantification of roof greening low-carbon landscape potential, we analyzed the internal carbon cycle mechanism of green roof systems and explored four carbon reduction and sink pathways (P1-P4): biogenic carbon sink, embodied carbon, operational carbon, and bioenergy supply. Based on the dual performance indicators of normalized value of carbon emissions and carbon payback time, we summarized the normalized value measurement method of each pathway. The potential and characteristics of each pathway were quantified by extracting data from the literature. The results showed that the quantified potential values for P1 to P4 were 9.54, -2.26, 2.96 and 0.35 kg CO2·m-2·a-1, respectively, and that the potential values for each pathway were strongly influenced by plant types, climate, and other factors. The imperfect base database and the heterogeneity of assessment scenarios impacted the accuracy of the measurements. The integrated low carbon landscape potential of extensive green roofs was discussed in sub-scenarios, with the 40-year-life cycle integrated carbon reduction ranging from 92.24 to 433.42 kg CO2·m-2 and the carbon payback period ranging from 5 to 14 years. Finally, we summarized the problems in the assessment to facilitate future updates and improvements.

Using the Molecular Transmission Networks to Analyze the Epidemic Characteristics of HIV-1 CRF08_BC in Kunming, Yunnan.

HIV-1CRF08_BC is the most prevalent epidemic subtype among heterosexual (HET) and intravenous drug users (IDUs) in Kunming, Yunnan. Using the pol region of gene sequences derived from molecular epidemiological surveys, we developed a molecular transmission network for the purpose of analyzing its epidemiological characteristics, assessing its epidemiological trends, identifying its potential transmission relationships, and developing targeted interventions. HyPhy 2.2.4 was used to calculate pairwise genetic distances between sequences; GraphPad-Prism 8.0 was employed to determine the standard genetic distance; and Cytoscope 3.7.2 was applied to visualize the network. We used the network analysis tools to investigate network characteristics and the Molecular Complex Detection (MCODE) tool to observe the growth of the network. We utilized a logistic regression model to examine the factors influencing clustering and a zero-inflated Poisson model to investigate the factors influencing potential transmission links. At the standard genetic distance threshold of 0.008, 406 out of 858 study participants were clustered in 132 dissemination networks with a total network linkage of 868, and the number of links per sequence ranged from 1 to 19. The MCODE analysis identified three significant modular clusters in the networks, with network scores ranging from 4.9 to 7. In models of logistic regression, HET, middle-aged and elderly individuals, and residents of northern and southeastern Kunming were more likely to enter the transmission network. According to the zero-inflated Poisson model, age, transmission category, sampling year, marital status, and CD4+ T level had a significant effect on the size of links. The molecular clusters in Kunming's molecular transmission network are specific and aggregate to a certain extent. HIV-1 molecular network analysis provided information on local transmission characteristics, and these findings helped to determine the priority of transmission-reduction interventions.

Removal effect of typical pollutants from stormwater runoff in ecological ditches.

Ecological ditches are a typical ecological facility for controlling road stormwater runoff pollution; they mainly remove harmful pollutants from runoff through plant absorption, retention and sedimentation, ecological adsorption, and microbial action. In this paper, according to the transport form of rainwater in the ditches, the removal effects of two different types of ditches on nitrogen, phosphorus, heavy metals, and other pollutants were simulated under three conditions of rainfall, slow flow, and still water, respectively, and their operating characteristics were analyzed. The results showed that the removal rate of TN in the two ecological ditches under slow flow conditions showed a downward trend as a whole with the increase of hydraulic load, and the suitable hydraulic load for TN removal should be selected as 0.3 m3/(m2 day). Under the simulated rainfall conditions, the TN removal rates of no. 1 and no. 2 ditches were 26.1-37.2% and 24.9 ~ 52.5%, respectively, and the TP removal rates were 44.6 ~ 63.3% and 36.1 ~ 62.1%. After 19.4 h and 22.1 h in the static state, the TP concentration in no. 1 ditch and no. 2 ditch reached the surface V water standard, and the average removal rate of TP was 74.7% and 53.7%, respectively. This paper provides a reference for selecting suitable parameters and optimizing the operational performance of ecological ditches to reduce runoff pollutants more effectively.

Government is expected to lead the payment of heat-resilient infrastructure.

Urban heat is severe in numerous cities, but the urgency of heat action and support for the development of heat-resilient infrastructure is unclear. To address these research gaps, this study investigated the perceived urgency of developing heat-resilient infrastructure and associated payment issues in eight megacities, in China using a questionnaire survey of 3758 respondents in August 2020. Overall, the respondents thought it was moderately urgent to take actions to address heat-related challenges. The development of mitigation and adaptation infrastructure is urgent. About 86.4% of the 3758 respondents expected the government to be involved in paying for heat-resilient infrastructure, but 41.2% supported cost-sharing among the government, developers, and owners. There were 1299 respondents willing to pay, resulting in an average annual payment of 44.06 RMB in a conservative scenario. This study is important for decision-makers to formulate plans on heat-resilient infrastructure and to release financial strategies for collecting investments and funds.

Tumor necrosis factor-related lncRNAs predict prognosis and immunotherapy response for patients with lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) has become one of the most lethal cancers, for which the recurrence and survival rates remain unfavorable. The tumor necrosis factor (TNF) family is involved in tumorigenesis and tumor progression. Various long non-coding RNAs (lncRNAs) play important roles by mediating the TNF family in cancer. Therefore, this study aimed to construct a TNF-related lncRNA signature to predict prognosis and immunotherapy response in LUAD. Methods: The expression of TNF family members and their related lncRNAs in a total of 500 enrolled LUAD patients was collected from The Cancer Genome Atlas (TCGA). Univariate Cox and the least absolute shrinkage and selection operator (LASSO)-Cox analysis was used to construct a TNF family-related lncRNA prognostic signature. Kaplan-Meier (KM) survival analysis was used to evaluate survival status. The time-dependent area under the receiver operating characteristic (ROC) curve (AUC) values were used to assess the predictive value of the signature to 1-, 2-, and 3-year overall survival (OS). Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify the signature-related biological pathways. Furthermore, tumor immune dysfunction and exclusion (TIDE) analysis was employed to evaluate immunotherapy response. Results: A total of 8 TNF-related lncRNAs significantly associated with OS of LUAD patients were used to construct a TNF family-related lncRNA prognostic signature. According to risk score, these patients were divided into high- and low-risk subgroups. The KM survival analysis indicated that patients in the high-risk group showed significantly less favorable OS than that of low-risk group. The AUC values in predicting 1-, 2-, and 3-year OS were 0.740, 0.738, and 0.758, respectively. Moreover, the GO and KEGG pathway analyses demonstrated that these lncRNAs were closely involved in immune-related signaling pathways. The further TIDE analysis indicated that high-risk patients had a lower TIDE score than that of low-risk patients, indicating that high-risk patients may be appropriate candidates for immunotherapy. Conclusions: For the first time, this study constructed and validated a prognostic predictive signature of LUAD patients based on TNF-related lncRNAs, and the signature showed good performance to predict immunotherapy response. Therefore, this signature may provide new strategies for individualized treatment of LUAD patients.

Yishen Huashi granule modulated lipid metabolism in diabetic nephropathy via PI3K/AKT/mTOR signaling pathways.

Aim: Diabetic nephropathy (DN) is the primary cause of end-stage renal disease worldwide. Although etiology for DN is complex and still needs to be fully understood, lipid metabolism disorder is found to play a role in it. Previously, we found Yishen Huashi (YSHS) granule could inhibit diabetic damage and reduce level of microalbuminuria (mALB) in DN animals. To explore its role and mechanism in lipid metabolism under DN settings, this study was designed. Materials and methods: DN rats were induced by streptozotocin (STZ), HepG2 and CaCO2 cells were applied for in vitro study. Hematoxylin-Eosin (HE), periodic acid-Schiff (PAS) staining, and Transmission Electron Microscopy (TEM) were applied for histological observation; 16s Sequencing was used for intestinal microbiota composition analysis; western blotting (WB) and immunofluorescence were carried out for molecular biological study, and enzyme-linked immunosorbent assay (ELISA) was used for lipid determination. Results: YSHS administration significantly reduced levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL-C), while increased level of high-density lipoprotein (HDL-C); meanwhile, histological changes and steatosis of the liver was ameliorated, integrity of the intestinal barrier was enhanced, and dysbacteriosis within intestinal lumen was ameliorated. Mechanism study found that YSHS modulated mitophagy within hepatocytes and inhibited mTOR/AMPK/PI3K/AKT signaling pathway. Conclusion: In conclusion, we found in the present study that YSHS administration could ameliorate lipid metabolism disorder in DN animals, and its modulation on intestinal-liver axis played a significant role in it.

The Role and Mechanism of Transglutaminase 2 in Regulating Hippocampal Neurogenesis after Traumatic Brain Injury.

Traumatic brain injury usually results in neuronal loss and cognitive deficits. Promoting endogenous neurogenesis has been considered as a viable treatment option to improve functional recovery after TBI. However, neural stem/progenitor cells (NSPCs) in neurogenic regions are often unable to migrate and differentiate into mature neurons at the injury site. Transglutaminase 2 (TGM2) has been identified as a crucial component of neurogenic niche, and significantly dysregulated after TBI. Therefore, we speculate that TGM2 may play an important role in neurogenesis after TBI, and strategies targeting TGM2 to promote endogenous neural regeneration may be applied in TBI therapy. Using a tamoxifen-induced Tgm2 conditional knockout mouse line and a mouse model of stab wound injury, we investigated the role and mechanism of TGM2 in regulating hippocampal neurogenesis after TBI. We found that Tgm2 was highly expressed in adult NSPCs and up-regulated after TBI. Conditional deletion of Tgm2 resulted in the impaired proliferation and differentiation of NSPCs, while Tgm2 overexpression enhanced the abilities of self-renewal, proliferation, differentiation, and migration of NSPCs after TBI. Importantly, injection of lentivirus overexpressing TGM2 significantly promoted hippocampal neurogenesis after TBI. Therefore, TGM2 is a key regulator of hippocampal neurogenesis and a pivotal therapeutic target for intervention following TBI.

Co-occurrence of urban heat and the COVID-19: Impacts, drivers, methods, and implications for the post-pandemic era.

Cities, the main place of human settlements, are under various mega challenges such as climate change, population increase, economic growth, urbanization, and pandemic diseases, and such challenges are mostly interlinked. Urban heat, due to heatwaves and heat islands, is the combined effect of climate change and urbanization. The COVID-19 is found to be a critical intervention of urban heat. However, the interrelationship between COVID-19 and urban heat has not been fully understood, constraining urban planning and design actions for improving the resilience to the dual impacts of heat and the pandemic. To close this research gap, this paper conducted a review on the co-occurrence of urban heat and the COVID-19 pandemic for a better understanding of their synergies, conflicts or trade-offs. The research involves a systematic review of urban temperature anomalies, variations in air pollutant concentrations, unbalanced energy development, and thermal health risks during the pandemic lockdown. In addition, this paper further explored data sources and analytical methods adopted to screen and identify the interventions of COVID-19 to urban heat. Overall, this paper is of significance for understanding the impact of COVID-19 on urban heat and provides a reference for coping with urban heat and the pandemic simultaneously. The world is witnessing the co-existence of heat and the pandemic, even in the post-pandemic era. This study can enlighten city managers, planners, the public, and researchers to collaborate for constructing a robust and resilient urban system for dealing with more than one challenges.

Bifidobacterium spp. as functional foods: A review of current status, challenges, and strategies.

Members of Bifidobacterium are among the first microbes to colonize the human intestine naturally, their abundance and diversity in the colon are closely related to host health. Recently, the gut microbiota has been gradually proven to be crucial mediators of various metabolic processes between the external environment and the host. Therefore, the health-promoting benefits of Bifidobacterium spp. and their applications in food have gradually been widely concerned. The main purpose of this review is to comprehensively introduce general features, colonization methods, and safety of Bifidobacterium spp. in the human gut, highlighting its health benefits and industrial applications. On this basis, the existing limitations and scope for future research are also discussed. Bifidobacteria have beneficial effects on the host's digestive system, immune system, and nervous system. However, the first prerequisite for functioning is to have enough live bacteria before consumption and successfully colonize the colon after ingestion. At present, strain breeding, optimization (e.g., selecting acid and bile resistant strains, adaptive evolution, high cell density culture), and external protection technology (e.g., microencapsulation and protectants) are the main strategies to address these challenges in food application.

Chaetoglobosin E inhibits tumor growth and promotes the anti-tumor efficacy of cytotoxic drugs in esophageal squamous cell carcinoma by targeting PLK1.

Background: Currently, there is no satisfactory treatment available for esophageal squamous cell carcinoma (ESCC), and thus, there is a pressing need to develop effective drugs. Chaetoglobosin E, a cytochalasan alkaloid derived from metabolites of Chaetomium madrasense 375, is a chaetoglobosin with intense anti-tumor activity. Therefore, revealing its anti-tumor mechanism for the application of cytochalasans is crucial. Methods: The cytotoxic effect of chaetoglobosin E and cisplatin on esophageal cancer KYSE-30, KYSE-150, and TE-1 cells was detected using cell viability or colony formation assays. The cell cycle, apoptosis, autophagy, invasion, and metastasis were assayed by flow cytometry or western blot. The potential target of chaetoglobosin E was assayed by RNA sequencing (RNA-seq) and large loop prediction software analysis and was assessed by western blot and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of its target on cell pyroptosis was assayed using overexpression and silence experiments. Results: Chaetoglobosin E significantly inhibited the proliferation of KYSE-30, KYSE-150, and TE-1 cells, especially KYSE-30 cells. Our results showed that chaetoglobosin E induced the G2/M phase arrest of KYSE-30 cells, followed by the down-regulation of cyclinB1, CDC2, and p-CDC2, and up-regulation of p21. Moreover, chaetoglobosin E also decreased the anti-apoptotic protein expression of Bcl-2, increased apoptotic expression of Bax, increased autophagy protein expressions of beclin1 and LC3, decreased invasion and metastasis protein expression of E-cadherin, and increased expression of vimentin. The RNA-seq and large loop prediction software analysis results indicated that its potential target might be polo-like kinase 1 (PLK1). Moreover, results also showed that chaetoglobosin E can reverse the PLK1 overexpression plasmid-induced up-regulation of the PLK1 protein. Furthermore, we found that chaetoglobosin E induced pyroptosis via the activation of the gasdermin E (GSDME) protein. Further studies showed that the high expression of PLK1 inactivated the GSDME protein, while the knockdown of PLK1 expression activated the GSDME protein, indicating that chaetoglobosin E induced cell pyroptosis by inhibiting PLK1. Conclusions: This study suggested that chaetoglobosin E may be a novel lead compound to the treatment of ESCC patients by targeting PLK1, and elucidated for the first time that PLK1 was involved in a new pyroptosis mechanism.

lncRNA HHIP-AS1/HHIP modulates osteogenic differentiation of BM-MSCs by regulating Hedgehog signaling pathway.

BACKGROUND: lncRNA, a type of non-coding RNA, plays an important role in the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs). In this study, lncRNA and mRNA microarrays were performed to study the change of gene expression during osteogenic differentiation of BM-MSCs. We focused on Hedgehog interacting protein (HHIP), because HHIP mRNA and lncRNA HHIP-AS1 were gradually down-regulated on days 0, 7, and 14 during osteogenic differentiation. In addition, the gene coding lncRNA HHIP-AS1 is located on the anti-sense of Hhip gene, implying the potential interaction between lncRNA HHIP-AS1 and HHIP mRNA. METHODS: BM-MSCs with over-expressed or silenced lncRNA HHIP-AS1 were constructed to explore the biological role of HHIP-AS1 in osteogenic differentiation. BM-MSCs were lysed to determine the alkaline phosphatase activity. Fluorescence in situ hybridization and immunofluorescence were performed to analyze HHIP-AS1, HHIP, RUNX2 and osteocalcin. RESULTS: Overexpression of lncRNA HHIP-AS1 increased HHIP expression, which suppressed Hedgehog signaling pathway, as indicated by the reduction of SMO, Gli1 and Gli2. The suppression of Hedgehog signal was associated with the inhibited osteogenesis. HHIP knockdown abolished the suppression of osteogenesis induced by lncRNA HHIP-AS1 overexpression. Through binding to HHIP mRNA, lncRNA HHIP-AS1 recruited ELAVL1 to HHIP mRNA, whereby increasing the mRNA stability and the protein level. CONCLUSIONS: This study revealed that down-regulation of HHIP due to lncRNA HHIP-AS1 reduction promoted the osteogenic differentiation of BM-MSCs though removing the suppression of Hedgehog signal.

Assessment of walkability and walkable routes of a 15-min city for heat adaptation: Development of a dynamic attenuation model of heat stress.

Actively addressing urban heat challenges is an urgent task for numerous cities. Existing studies have primarily developed heat mitigation strategies and analyzed their cooling performance, while the adaptation strategies are far from comprehensive to protect citizens from heat-related illnesses and deaths. To address this research gap, this paper aims to enhance people's adaptation capacity by investigating walkability within fifteen-minute cities (FMC). Taking cognizance of thermal comfort, health, and safety, this paper developed a dynamic attenuation model (DAM) of heat stress, along with heat stress aggravation, continuance, and alleviation. An indicator of remaining tolerant heat discomfort (R t ) was proposed with the integration of the Universal Thermal Climate Index (UTCI) to assess heat-related walkability. Following an empirical study among 128 residents in Mianyang, China, and assessing four levels of heat stress, the maximum tolerant heat discomfort was determined to be 60 min. Furthermore, the DAM was applied to an FMC with 12 neighborhoods in Fucheng, Mianyang, China. The results indicate that for each neighborhood, the street was generally walkable with an R t ranging between 15 and 30 min, after walking for 900 m. A population-based FMC walkability was further determined, finding that the core area of the FMC was favorable for walking with an R t of 45-46 min, and the perpetual areas were also walkable with an R t of 15-30 min. Based on these results, suggestions on the frequency of public services (frequently used, often used, and occasionally used) planning were presented. Overall, this paper provides a theoretical model for analyzing walkability and outlines meaningful implications for planning heat adaptation in resilient, safe, comfortable, and livable FMCs.