Intermittent hypoxia training enhances Aß endocytosis by plaque associated microglia via VPS35-dependent TREM2 recycling in murine Alzheimer's disease.

BACKGROUND: Beta-amyloid (Aß) deposition in the brain parenchyma is a crucial initiating step in the amyloid cascade hypothesis of Alzheimer's disease (AD) pathology. Furthermore, dysfunction of plaque-associated microglia, also known as disease-associated microglia (DAM) has been reported to accelerate Aß deposition and cognitive impairment. Our previous research demonstrated that intermittent hypoxia training (IHT) improved AD pathology by upregulating autophagy in DAM, thereby enhancing oligomeric Aß (oAß) clearance. Considering that oAß internalization is the initial stage of oAß clearance, this study focused on the IHT mechanism involved in upregulating Aß uptake by DAM. METHODS: IHT was administered to 8-month-old APP/PS1 mice or 6-month-old microglial vacuolar protein sorting 35 (VPS35) knockout mice in APP/PS1 background (MG VPS35 KO: APP/PS1) for 28 days. After the IHT, the spatial learning-memory capacity of the mice was assessed. Additionally, AD pathology was determined by estimating the nerve fiber and synapse density, Aß plaque deposition, and Aß load in the brain. A model of Aß-exposed microglia was constructed and treated with IHT to explore the related mechanism. Finally, triggering receptor expressed on myeloid cells 2 (TREM2) intracellular recycling and Aß internalization were measured using a fluorescence tracing technique. RESULTS: Our results showed that IHT ameliorated cognitive function and Aß pathology. In particular, IHT enhanced Aß endocytosis by augmenting the intracellular transport function of microglial TREM2, thereby contributing to Aß clearance. Furthermore, IHT specifically upregulated VPS35 in DAM, the primary cause for the enhanced intracellular recycling of TREM2. IHT lost ameliorative effect on Aß pathology in MG VPS35 KO: APP/PS1 mice brain. Lastly, the IHT mechanism of VPS35 upregulation in DAM was mediated by the transcriptional regulation of VPS35 by transcription factor EB (TFEB). CONCLUSION: IHT enhances Aß endocytosis in DAM by upregulating VPS35-dependent TREM2 recycling, thereby facilitating oAß clearance and mitigation of Aß pathology. Moreover, the transcriptional regulation of VPS35 by TFEB demonstrates a close link between endocytosis and autophagy in microglia. Our study further elucidates the IHT mechanism in improving AD pathology and provides evidence supporting the potential application of IHT as a complementary therapy for AD.

[TFEB activator 1 enhances autophagic degradation of oligomeric amyloid-ß in microglia].

The purpose of the study was to investigate the mechanism of TFEB activator 1 (TA1) improving the autophagic degradation of oligomeric amyloid-ß (oAß) in microglia, and to explore the therapeutic effect of TA1 on an in vitro model of microglia in Alzheimer's disease (AD). Primary microglia were exposed to 1 µmol/L oAß for 0, 3, 12, and 24 h respectively to construct the in vitro model of microglia in AD. In order to explore the therapeutic effect of TA1, primary microglia were co-treated with 1 µmol/L oAß and 1 µmol/L TA1 for 12 h. To determine the autophagy flux, the above cells were further treated with 100 nmol/L Bafilomycin A1 for 1 h before fixation. Fluorescent probes were used to detect the endocytosis or degradation of oAß1-42 by microglia. The autophagic flux was determined by infection of lentivirus mCherry-EGFP-LC3. The nuclear TFEB intensity, the autophagosomes number, and the colocalization ratio of oAß1-42 with lysosome-associated membrane protein 1 (LAMP1) or microtubule-associated protein light chain 3 (LC3), were detected by immunofluorescence assay. Expressions of autophagy-related-genes, including Lamp1, Atg5, and Map1lc3b, were detected by qRT-PCR. Results showed that prolonged oAß exposure inhibited the endocytosis and degradation of oAß by microglia. Meanwhile, the number of autophagosomes and autophagy flux in microglia decreased after 12 h of oAß treatment. We further found that the nuclear expression of autophagy regulator TFEB decreased after 12 h of oAß exposure, resulting in the decrease of autophagy genes, thus leading to the damage of autophagic degradation of oAß. Therefore, long-term oAß exposure was considered to construct the in vitro model of microglia in AD. After TA1 treatment, the nuclear expression of TFEB in cells was obviously upregulated. TA1 treatment upregulated the expressions of autophagy-related genes, leading to the recovery of autophagy flux. TA1 also recovered the endocytosis and degradation of oAß by microglia. In conclusion, TA1 could improve oAß clearance by microglia in AD by upregulating microglial TFEB-mediated autophagy, suggesting TA1 as a potential therapeutic drug for AD.

Deciphering the interaction mechanism between soy protein isolate and fat-soluble anthocyanin on experiments and molecular simulations.

In this work, the acylated anthocyanin (Ca-An) was prepared by enzymatic modification of black rice anthocyanin with caffeic acid, and the binding mechanism of Ca-An to soybean protein isolate (SPI) was investigated by experiments and computer simulation to expand the potential application of anthocyanin in food industry. Multi-spectroscopic studies revealed that the stable binding of Ca-An to SPI induced the folding of protein polypeptide chain, which transformed the secondary structure of SPI trended to be flexible. The microenvironment of protein was transformed from hydrophobic to hydrophilic, while tyrosine played dominant role in quenching process. The binding sites and forces of the complexes were determined by computer simulation for further explored. The protein conformation of the 7S and 11S binding regions to Ca-An changed, and the amino acid microenvironment shifted to hydrophilic after binding. The results showed that more non-polar amino acids existed in the binding sites, while in binding process van der Waals forces and hydrogen bonding played a major role hydrophobicity played a minor role. Based on MM-PBSA analysis, the binding constants of 7S-Ca-An and 11S-Ca-An were 0.518 × 106 mol-1 and 5.437 × 10-3 mol-1, respectively. This information provides theoretical guidance for further studying the interaction between modified anthocyanins and biomacromolecules.

Soil microbiome of shiro reveals the symbiotic relationship between Tricholoma bakamatsutake and Quercus mongolica.

Tricholoma bakamatsutake is a delicious and nutritious ectomycorrhizal fungus. However, its cultivation is hindered owing to limited studies on its symbiotic relationships. The symbiotic relationship between T. bakamatsutake and its host is closely related to the shiro, a complex network composed of mycelium, mycorrhizal roots, and surrounding soil. To explore the symbiotic relationship between T. bakamatsutake and its host, soil samples were collected from T. bakamatsutake shiro (Tb) and corresponding Q. mongolica rhizosphere (CK) in four cities in Liaoning Province, China. The physicochemical properties of all the soil samples were then analyzed, along with the composition and function of the fungal and bacterial communities. The results revealed a significant increase in total potassium, available nitrogen, and sand in Tb soil compared to those in CK soil, while there was a significant decrease in pH, total nitrogen, total phosphorus, available phosphorus, and silt. The fungal community diversity in shiro was diminished, and T. bakamatsutake altered the community structure of its shiro by suppressing other fungi, such as Russula (ectomycorrhizal fungus) and Penicillium (phytopathogenic fungus). The bacterial community diversity in shiro increased, with the aggregation of mycorrhizal-helper bacteria, such as Paenibacillus and Bacillus, and plant growth-promoting bacteria, such as Solirubrobacter and Streptomyces, facilitated by T. bakamatsutake. Microbial functional predictions revealed a significant increase in pathways associated with sugar and fat catabolism within the fungal and bacterial communities of shiro. The relative genetic abundance of carboxylesterase and gibberellin 2-beta-dioxygenase in the fungal community was significantly increased, which suggested a potential symbiotic relationship between T. bakamatsutake and Q. mongolica. These findings elucidate the microbial community and relevant symbiotic environment to better understand the relationship between T. bakamatsutake and Q. mongolica.

Poor clinical outcomes and immunoevasive contexture in CD161+CD8+ T cells barren human pancreatic cancer.

BACKGROUND: The role of CD161 expression on CD8+ T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161+CD8+ T cells in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study seeks to clarify the prognostic value and molecular characteristics linked to CD161+CD8+ T cell infiltration in PDAC. METHODS: This study included 186 patients with confirmed PDAC histology after radical resection. CD161+CD8+ T cell infiltration was assessed using immunofluorescence staining on tumor microarrays. Flow cytometry and single-cell RNA sequencing were used to evaluate their functional status. RESULTS: We observed significant associations between tumor-infiltrating CD161+CD8+ T cells and clinicopathological factors, such as tumor differentiation, perineural invasion, and serum CA19-9 levels. Patients with higher tumor-infiltrating CD161+CD8+ T cell levels had longer overall survival (OS) and recurrence-free survival (RFS) than those with lower levels. Multivariable analysis confirmed tumor-infiltrating CD161+CD8+ T cell as an independent prognostic indicator for both OS and RFS. Notably, a combination of tumor-infiltrating CD161+CD8+ T cell and CA19-9 levels showed a superior power for survival prediction, and patients with low tumor-infiltrating CD161+CD8+ T cell and high CA19-9 levels had the worst survival. Furthermore, lower tumor-infiltrating CD161+CD8+ T cells were associated with a better response to adjuvant chemotherapy. Finally, we identified tumor-infiltrating CD161+CD8+ T cells as a unique subtype of responsive CD8+ T cells characterized by increased levels of cytotoxic cytokines and immune checkpoint molecules. CONCLUSION: CD161+CD8+ T cells exhibit elevated levels of both cytotoxic and immune-checkpoint molecules, indicating as a potential and attractive target for immunotherapy. The tumor-infiltrating CD161+CD8+ T cell is a valuable and promising predictor for survival and therapeutic response to adjuvant chemotherapy in PDAC. Further research is warranted to validate its role in the risk stratification and optimization of therapeutic strategies.

Recent advances in nanomedicine for metabolism-targeted cancer therapy.

Metabolism denotes the sum of biochemical reactions that maintain cellular function. Different from most normal differentiated cells, cancer cells adopt altered metabolic pathways to support malignant properties. Typically, almost all cancer cells need a large number of proteins, lipids, nucleotides, and energy in the form of ATP to support rapid division. Therefore, targeting tumour metabolism has been suggested as a generic and effective therapy strategy. With the rapid development of nanotechnology, nanomedicine promises to have a revolutionary impact on clinical cancer therapy due to many merits such as targeting, improved bioavailability, controllable drug release, and potentially personalized treatment compared to conventional drugs. This review comprehensively elucidates recent advances of nanomedicine in targeting important metabolites such as glucose, glutamine, lactate, cholesterol, and nucleotide for effective cancer therapy. Furthermore, the challenges and future development in this area are also discussed.

Particulate polycyclic aromatic hydrocarbons in rural households burning solid fuels in Xuanwei County, Southwest China: occurrence, size distribution, and health risks.

The study is about the size distribution and health risks of polycyclic aromatic hydrocarbons (PAHs) in indoor environment of Xuanwei, Southwest China particle samples were collected by Anderson 8-stage impactor which was used to gather particle samples to nine size ranges. Size-segregated samples were collected in indoor from a rural village in Xuanwei during the non-heating and heating seasons. The results showed that the total concentrations of the indoor particulate matter (PM) were 757 ± 60 and 990 ± 78 µg/m3 in non-heating and heating seasons, respectively. The total concentration of indoor PAHs reached to 8.42 ± 0.53 µg/m3 in the heating season, which was considerably greater than the concentration in the non-heating season (2.85 ± 1.72 µg/m3). The size distribution of PAHs showed that PAHs were mainly enriched in PMs with the diameter <1.1 µm. The diagnostic ratios (DR) and principal component analysis (PCA) showed that coal and wood for residential heating and cooking were the main sources of indoor PAHs. The results of the health risk showed that the total deposition concentration (DC) in the alveolar region (AR) was 0.25 and 0.68 µg/m3 in the non-heating and heating seasons respectively. Throughout the entire sampling periods, the lifetime cancer risk (R) based on DC of children and adults varied between 3.53 ×10-5 to 1.79 ×10-4. During the heating season, the potential cancer risk of PAHs in adults was significant, exceeding 10-4, with a rate of 96%.

Aptamer Conjugate-Based Ratiometric Fluorescent Probe for Precise Imaging of Therapy-Induced Cancer Senescence.

Therapy-induced cellular senescence has been increasingly recognized as a key mechanism to promote various aspects of carcinogenesis in a nonautonomous manner. Thus, real-time imaging monitoring of cellular senescence during cancer therapy is imperative not only to further elucidate its roles in cancer progression but also to provide guidance for medical management of cancer. However, it has long been a challenging task due to the lack of effective imaging molecule tools with high specificity and accuracy toward cancer senescence. Herein, we report the rational design, synthesis, and evaluation of an aptamer conjugate-based ratiometric fluorescent probe for precise imaging of therapy-induced cancer senescence. Unlike traditional senescence imaging systems, our probe targets two senescence-associated markers at both cellular and subcellular dimensions, namely, aptamer-mediated membrane marker recognition for active cell targeting and lysosomal marker-triggered ratiometric fluorescence changes of two cyanine dyes for site-specific, high-contrast imaging. Moreover, such a two-channel fluorescence response is activated after a one-step reaction and at the same location, avoiding the diffusion-caused signal decay previously encountered in dual-marker activated probes, contributing to spatiotemporally specific imaging of therapy-induced cancer senescence in living cells and three-dimensional multicellular tumor spheroids. This work may offer a valuable tool for a basic understanding of cellular senescence in cancer biology and interventions.

Tumor Microenvironment Responsive CD8+ T Cells and Myeloid-Derived Suppressor Cells to Trigger CD73 Inhibitor AB680-Based Synergistic Therapy for Pancreatic Cancer.

CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti-PD-1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8+ T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid-derived suppressor cells (MDSCs) by tumor-derived CXCL5 in an AMP-dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD-1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8+ T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD-1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC.

Intermittent hypoxia therapy ameliorates beta-amyloid pathology via TFEB-mediated autophagy in murine Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Impaired autophagy in plaque-associated microglia (PAM) has been reported to accelerate amyloid plaque deposition and cognitive impairment in AD pathogenesis. Recent evidence suggests that the transcription factor EB (TFEB)-mediated activation of the autophagy-lysosomal pathway is a promising treatment approach for AD. Moreover, the complementary therapy of intermittent hypoxia therapy (IHT) has been shown to upregulate autophagy and impart beneficial effects in patients with AD. However, the effect of IHT on PAM remains unknown. METHODS: 8-Month-old APP/PS1 mice were treated with IHT for 28 days. Spatial learning memory capacity and anxiety in mice were investigated. AD pathology was determined by the quantity of nerve fibers and synapses density, numbers of microglia and neurons, Aß plaque deposition, pro-inflammatory factors, and the content of Aß in the brain. TFEB-mediated autophagy was determined by western blot and qRT-PCR. Primary microglia were treated with oligomeric Aß 1-42 (oAß) combined with IHT for mechanism exploration. Differential genes were screened by RNA-seq. Autophagic degradation process of intracellular oAß was traced by immunofluorescence. RESULTS: In this study, we found that IHT ameliorated cognitive function by attenuating neuronal loss and axonal injury in an AD animal model (APP/PS1 mice) with beta-amyloid (Aß) pathology. In addition, IHT-mediated neuronal protection was associated with reduced Aß accumulation and plaque formation. Using an in vitro PAM model, we further confirmed that IHT upregulated autophagy-related proteins, thereby promoting the Aß autophagic degradation by PAM. Mechanistically, IHT facilitated the nuclear localization of TFEB in PAM, with TFEB activity showing a positive correlation with Aß degradation by PAM in vivo and in vitro. In addition, IHT-induced TFEB activation was associated with the inhibition of the AKT-MAPK-mTOR pathway. CONCLUSIONS: These results suggest that IHT alleviates neuronal damage and neuroinflammation via the upregulation of TFEB-dependent Aß clearance by PAM, leading to improved learning and memory in AD mice. Therefore, IHT may be a promising non-pharmacologic therapy in complementary medicine against AD.

Polymer and Hybrid Optical Devices Manipulated by the Thermo-Optic Effect.

The thermo-optic effect is a crucial driving mechanism for optical devices. The application of the thermo-optic effect in integrated photonics has received extensive investigation, with continuous progress in the performance and fabrication processes of thermo-optic devices. Due to the high thermo-optic coefficient, polymers have become an excellent candidate for the preparation of high-performance thermo-optic devices. Firstly, this review briefly introduces the principle of the thermo-optic effect and the materials commonly used. In the third section, a brief introduction to the waveguide structure of thermo-optic devices is provided. In addition, three kinds of thermo-optic devices based on polymers, including an optical switch, a variable optical attenuator, and a temperature sensor, are reviewed. In the fourth section, the typical fabrication processes for waveguide devices based on polymers are introduced. Finally, thermo-optic devices play important roles in various applications. Nevertheless, the large-scale integrated applications of polymer-based thermo-optic devices are still worth investigating. Therefore, we propose a future direction for the development of polymers.

Adulthood bisphenol A exposure induces anxiety in male mice via downregulation of alpha-1D adrenergic receptor in paraventricular thalamus.

Bisphenol A (BPA), a ubiquitous endocrine disrupting chemical, is widely used in household plastic products. Large amounts of evidence indicate prenatal and postnatal BPA exposure causes neurodevelopmental disorders such as anxiety and autism. However, the neuronal mechanisms underlying the neurotoxic effects of adulthood BPA exposure remain poorly understood. Here, we provided evidences that adult mice treated with BPA (0.45 mg/kg/day) during 3 weeks exhibited sex-specific anxiety like behaviors. We demonstrated that the BPA-induced anxiety in male mice, but not in female mice, was closely associated with hyperactivity of glutamatergic neurons in the paraventricular thalamus (PVT). Acute chemogenetic activation of PVT glutamatergic neurons caused similar effects on anxiety as observed in male mice exposed to BPA. In contrast, acute chemogenetic inhibition of PVT glutamatergic neurons reduced BPA-induced anxiety in male mice. Concomitantly, the BPA-induced anxiety was related with a down-regulation of alpha-1D adrenergic receptor in the PVT. Taken together, the present study indicated a previously unknown target region in the brain for neurotoxic effects of BPA on anxiety and implicated a possible molecular mechanism of action.

Ultralight, Heat-Insulated, and Tough PVA Hydrogel Hybridized with SiO2 @cellulose Nanoclaws Aerogel via the Synergy of Hydrophilic and Hydrophobic Interfacial Interactions.

Lightweight porous hydrogels provide a worldwide scope for functional soft mateirals. However, most porous hydrogels have weak mechanical strength, high density (>1 g cm-3 ), and high heat absorption due to weak interfacial interactions and high solvent fill rates, which severely limit their application in wearable soft-electronic devices. Herein, an effective hybrid hydrogel-aerogel strategy to assemble ultralight, heat-insulated, and tough polyvinyl alcohol (PVA)/SiO2 @cellulose nanoclaws (CNCWs) hydrogels (PSCG) via strong interfacial interactions with hydrogen bonding and hydrophobic interaction is demonstrated. The resultant PSCG has an interesting hierarchical porous structure from bubble template (≈100 µm), PVA hydrogels networks introduced by ice crystals (≈10 µm), and hybrid SiO2 aerogels (<50 nm), respectively. PSCG shows unprecedented low density (0.27 g cm-3 ), high tensile strength (1.6 MPa) & compressive strength (1.5 MPa), excellent heat-insulated ability, and strain-sensitive conductivity. This lightweight porous and tough hydrogel with an ingenious design provides a new way for wearable soft-electronic devices.

Survival benefit and impact of adjuvant chemotherapy following systemic neoadjuvant chemotherapy in patients with resected pancreas ductal adenocarcinoma: a retrospective cohort study.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) are increasingly receiving systemic neoadjuvant chemotherapy (NAC), particularly those with borderline resectable and locally advanced disease. However, the specific role of additional adjuvant chemotherapy (AC) in these patients is unknown. The objective of this study is to further assess the clinical benefit and impact of systemic AC in patients with resected PDAC after NAC. METHODS: Data on PDAC patients with or without AC following systemic NAC and surgical resection were retrospectively retrieved from the Surveillance, Epidemiology, and End Results (SEER) database between 2006 and 2019. A matched cohort was created using propensity score matching (PSM), and baseline characteristics were balanced to reduce bias. Overall survival (OS) and cancer-specific survival (CSS) were calculated using matching cohorts. RESULTS: The study enrolled a total of 1589 patients, with 623 (39.2%) in the AC group and 966 (51.8%) in the non-AC group [mean age, 64.0 (9.9) years; 766 (48.2%) were females and 823 (51.8%) were males]. All patients received NAC, and among the crude population, 582 (36.6%) received neoadjuvant radiotherapy, while 168 (10.6%) received adjuvant radiotherapy. Following the 1:1 PSM, 597 patients from each group were evaluated further. The AC and non-AC groups had significantly different median OS (30.0 vs. 25.0 months, P =0.002) and CSS (33.0 vs. 27.0 months, P =0.004). After multivariate Cox regression analysis, systemic AC was independently associated with improved survival ( P =0.003, HR=0.782; 95% CI, 0.667-0.917 for OS; P =0.004, HR=0.784; 95% CI, 0.663-0.926 for CSS), and age, tumor grade, and AJCC N staging were also independent predictors of survival. Only patients younger than 65 years old and those with a pathological N1 category showed a significant association between systemic AC and improved survival in the subgroup analysis adjusted for these covariates. CONCLUSION: Systemic AC provides a significant survival benefit in patients with resected PDAC following NAC compared to non-AC patients. Our study discovered that younger patients, patients with aggressive tumors and potentially well response to NAC might benefit from AC to achieve prolonged survival after curative tumor resection.

CX3CL1/CX3CR1 signal mediates M1-type microglia and accelerates high-altitude-induced forgetting.

Introduction: Hypoxia-induced neuronal damage is the primary cause of cognitive impairment induced by high-altitude exposure. Microglia play a crucial regulatory role in the central nervous system (CNS) homeostasis and synaptic plasticity. M1-type polarized microglia are suspected to be responsible for CNS injury under hypoxic conditions, but the exact molecular mechanism is still unelucidated. Methods: CX3CR1 knock out and wide type mice were exposed to a simulated plateau at 7000 m for 48 h to construct the model of hypobaric hypoxia-induced memory impairment. The memory impairment of mice was assessed by Morris water maze. The dendritic spine density in the hippocampus was examined by Golgi staining. The synapses in the CA1 region and the number of neurons in the DG region were examined by immunofluorescence staining. The synapses in microglia activation and phagocytosis were examined by immunofluorescence. The levels of CX3CL1/CX3CR1 and their downstream proteins were detected. CX3CR1 knockout primary microglia were treated with CX3CL1 combined with 1% O2. The levels of proteins related to microglial polarization, the uptake of synaptosome and phagocytotic ability of microglia were detected. Results: In this study, mice exposed to a simulated 7000 m altitude for 48 h developed significant amnesia for recent memories, but no significant change in their anxiety levels was observed. Hypobaric hypoxia exposure (7000 m altitude above sea level for 48 h) resulted in synapse loss in the CA1 region of the hippocampus, but no significant changes occurred in the total number of neurons. Meanwhile, microglia activation, increased phagocytosis of synapses by microglia, and CX3CL1/CX3CR1 signal activation were observed under hypobaric hypoxic exposure. Further, we found that after hypobaric hypoxia exposure, CX3CR1-deficient mice showed less amnesia, less synaptic loss in the CA1 region, and less increase in M1 microglia, compared to their wildtype siblings. CX3CR1-deficient microglia did not exhibit M1-type polarization in response to either hypoxia or CX3CL1 induction. Both hypoxia and CX3CL1 induced the phagocytosis of synapses by microglia through the upregulation of microglial phagocytosis. Discussion: The current study demonstrates that CX3CL1/CX3CR1 signal mediates the M1-type polarization of microglia under high-altitude exposure and upregulates microglial phagocytosis, which increases the phagocytosis of synapses in the CA1 region of the hippocampus, causing synaptic loss and inducing forgetting.

Design of Suspended Slot Racetrack Microring Refractive Index Sensor Based on Polymer Nanocomposite.

Recently, polymer nanocomposites have attracted great interest due to their remarkable characteristics of high performance and enabling production of low-cost devices. This article explores the reflective index sensing application of the polymer nanocomposite IOC-133, which is a TiOx/polymer nanocomposite with a reflective index between 1.8 and 1.9. Considering the material properties of high reflective index, low absorption loss, and compatibility with nanoimprint lithography, a microring-based reflective index sensor with a suspended slot waveguide structure is proposed. We combined the sensing mechanism of slot waveguides with high reflective index polymer nanocomposites and designed the suspended structure to address the problem of decreasing sensitivity caused by residual layers. The sensing device was adopted as a microring resonator, which is conducive to large-scale integration. The finite-difference time-domain (FDTD) method was employed to analyze the effects of several key parameters. The results showed that the racetrack microring sensor we propose can achieve a high sensitivity of 436 nm/RIU (Refractive Index Units), about six times higher than the microring sensor with a ridge waveguide. The Q factor of the microring reaches 1.42 × 104, and the detection limit is 1.38 × 10-4 RIU. The proposed suspended slot microring sensor has potential value in the field of nanoprinted photonic integrated circuits.

Dual-Parameter Recognition-Directed Design of the Activatable Fluorescence Probe for Precise Imaging of Cellular Senescence.

Specific imaging of cellular senescence emerges as a promising strategy for early diagnosis and treatment of various age-related diseases. The currently available imaging probes are routinely designed by targeting a single senescence-related marker. However, the inherently high heterogeneity of senescence makes them inaccessible to achieve specific and accurate detection of broad-spectrum cellular senescence. Here, we report the design of a dual-parameter recognition fluorescent probe for precise imaging of cellular senescence. This probe remains silent in non-senescent cells, yet produces bright fluorescence after sequential responses to two senescence-associated markers, namely, SA-ß-gal and MAO-A. In-depth studies reveal that this probe allows for high-contrast imaging of senescence, independent of the cell source or stress type. More impressively, such dual-parameter recognition design further allows it to distinguish senescence-associated SA-ß-gal/MAO-A from cancer-related ß-gal/MAO-A, compared to commercial or previous single-marker detection probes. This study offers a valuable molecular tool for imaging cellular senescence, which is expected to significantly expand the basic studies on senescence and facilitate advances of senescence-related disease theranostics.

[Spatiotemporal Dynamic Evolution and Gravity Center Migration of Carbon Emissions in the Main Urban Area of Chongqing over the Past 20 Years].

Global warming caused by carbon emissions is an environmental issue that is of great concern to all walks of life. Dynamic monitoring of the spatiotemporal evolution of urban carbon emissions is an important part of achieving the regional double-carbon goals. Taking the main urban area of Chongqing as an example, based on the data of land use and energy consumption, this study estimated the carbon emissions of 153 townships and streets in the main urban area of Chongqing from 2000 to 2020 by using the carbon emission coefficient method. Additionally, using the ESTDA framework to pass the LISA time path, spatiotemporal transition, and the standard deviation ellipse model from the perspective of spatiotemporal interaction, the spatiotemporal dynamic evolution of carbon emissions in the main urban area and the shift in the center of gravity over the past 20 years were analyzed. The results showed that: ① in the past 20 years, the carbon emissions in the main urban and rural areas have had a significant positive spatial correlation, and the spatial convergence showed a trend of first decreasing and then increasing. ② In the past 20 years, there were 126 township streets with low and medium relative lengths (accounting for 82%), indicating that the local spatial structure of township carbon emissions in the main urban area had strong stability; the total number of township streets with low and medium curvatures was 138 (accounting for 90%), indicating that the volatility of the main urban and rural carbon emissions in the direction of spatial dependence was relatively stable; there were 113 township streets (accounting for 74%) of the synergistic growth type, indicating that the main urban and rural carbon emissions were relatively stable. The emission pattern had strong spatial integration. ③ In the past 20 years, the spatiotemporal agglomeration index was greater than 70%, indicating that the local spatial correlation pattern and agglomeration characteristics of carbon emissions in the main urban and rural areas had strong stability. 4 In the past 20 years, the center of carbon emission in the main urban area had been distributed between 106°30'43″-106°32'42″E, 29°33'34″-29°35'56″N, and the center of gravity shifted to the northeast as a whole. The spatial distribution changed from the "northwest-southeast" pattern to the "northeast-southwest" pattern. These results can provide reference for the green and low-carbon sustainable development of Chongqing and the formulation of differentiated emission reduction policies, as well as provide reference for other similar mountain cities in western China.

Engineering Hierarchical Recognition-Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti-Atherosclerosis Therapy.

Precise regulation of vascular senescence represents a far-reaching strategy to combat age-related diseases. However, the high heterogeneity of senescence, alongside the lack of targeting and potent senolytics, makes it very challenging. Here we report a molecular design to tackle this challenge through multidimensional, hierarchical recognition of three hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state. Its potential for in vivo treatment of vascular diseases is successfully illustrated in a model of atherosclerosis, with effective suppression of the plaque progression yet negligible side effects.

Recent Advances in Strategies for Imaging Detection and Intervention of Cellular Senescence.

Cellular senescence is a stable cell cycle arrest state that can be triggered by a wide range of intrinsic or extrinsic stresses. Increased burden of senescent cells in various tissues is thought to contribute to aging and age-related diseases. Thus, the detection and interventions of senescent cells are critical for longevity and treatment of disease. However, the highly heterogeneous feature of senescence makes it challenging for precise detection and selective clearance of senescent cells in different age-related diseases. To address this issue, considerable efforts have been devoted to developing senescence-targeting molecular theranostic strategies, based on the potential biomarkers of cellular senescence. Herein, we review recent advances in the field of anti-senescence research and highlight the specific visualization and elimination of senescent cells. Additionally, the challenges in this emerging field are outlined.