The novel function of an orphan pheromone receptor reveals the sensory specializations of two potential distinct types of sex pheromones in noctuid moth.

Sex pheromones play crucial role in mating behavior of moths, involving intricate recognition mechanisms. While insect chemical biology has extensively studied type I pheromones, type II pheromones remain largely unexplored. This study focused on Helicoverpa armigera, a representative species of noctuid moth, aiming to reassess its sex pheromone composition. Our research unveiled two previously unidentified candidate type II sex pheromones-3Z,6Z,9Z-21:H and 3Z,6Z,9Z-23:H-in H. armigera. Furthermore, we identified HarmOR11 as an orphan pheromone receptor of 3Z,6Z,9Z-21:H. Through AlphaFold2 structural prediction, molecular docking, and molecular dynamics simulations, we elucidated the structural basis and key residues governing the sensory nuances of both type I and type II pheromone receptors, particularly HarmOR11 and HarmOR13. This study not only reveals the presence and recognition of candidate type II pheromones in a noctuid moth, but also establishes a comprehensive structural framework for PRs, contributing to the understanding of connections between evolutionary adaptations and the emergence of new pheromone types.

Population genomics analysis reveals footprints of selective breeding in a rapid-growth variety of Paulownia fortunei with apical dominance.

Paulownia fortunei is an ecologically and economically valuable tree cultivated for its rapid growth and high-quality timber. To enhance Paulownia germplasm, we have developed the elite variety QingT with patented advantages in growth rate and apical dominance. To illuminate the genetic basis of QingT's superior traits, here we harness comparative population genomics to analyze genomic variation patterns between QingT and common Paulownia. We performed whole-genome re-sequencing of 30 QingT and 30 common samples, detecting 15.6 million SNPs and 2.6 million indels. Phylogeny and population structure analyses robustly partitioned common and QingT into distinct groups which indicate robust genome stabilization. QingT exhibited reduced heterozygosity and linkage disequilibrium decay compared to common Paulownia, reflecting high recombination, indicating hybridizing effects with common white-flowered string is the source of its patented advantages. Genome selection scans uncovered 25 regions of 169 genes with elevated nucleotide diversity, indicating selection sweeps among groups. Functional analysis of sweep genes revealed upregulation of ribosomal, biosynthesis, and growth pathways in QingT, implicating enhanced protein production and developmental processes in its rapid growth phenotype. This study's insights comprehensively chart genomic variation during Paulownia breeding, localizing candidate loci governing agronomic traits, and underpinnings of future molecular breeding efforts to boost productivity.

Hi-C-guided many-polymer model to decipher 3D genome organization.

We propose a high-throughput chromosome conformation capture data-based many-polymer model that allows us to generate an ensemble of multi-scale genome structures. We demonstrate the efficacy of our model by validating the generated structures against experimental measurements and employ them to address key questions regarding genome organization. Our model first confirms a significant correlation between chromosome size and nuclear positioning. Specifically, smaller chromosomes are distributed at the core region, whereas larger chromosomes are at the periphery, interacting with the nuclear envelope. The spatial distribution of A- and B-type compartments, which is nontrivial to infer from the corresponding high-throughput chromosome conformation capture maps alone, can also be elucidated using our model, accounting for an issue such as the effect of chromatin-lamina interaction on the compartmentalization of conventional and inverted nuclei. In accordance with imaging data, the overall shape of the 3D genome structures generated from our model displays significant variation. As a case study, we apply our method to the yellow fever mosquito genome, finding that the predicted morphology displays, on average, a more globular shape than the previously suggested spindle-like organization and that our prediction better aligns with the fluorescence in situ hybridization data. Our model has great potential to be extended to investigate many outstanding issues concerning 3D genome organization.

Biomimetic Nanoplatform for Dual-Targeted Clearance of Activated and Senescent Cancer-Associated Fibroblasts to Improve Radiation Resistance in Breast Cancer.

Radiation resistance in breast cancer resulting in residual lesions or recurrence is a significant cause to radiotherapy failure. Cancer-associated fibroblasts (CAFs) and radiotherapy-induced senescent CAFs can further lead to radiation resistance and tumor immunosuppressive microenvironment. Here, an engineering cancer-cell-biomimetic nanoplatform is constructed for dual-targeted clearance of CAFs as well as senescent CAFs. The nanoplatform is prepared by 4T1 cell membrane vesicles chimerized with FAP single-chain fragment variable as the biomimetic shell for targeting of CAFs and senescent CAFs, and PLGA nanoparticles (NPs) co-encapsulated with nintedanib and ABT-263 as the core for clearance of CAFs and senescent CAFs, which are noted as FAP-CAR-CM@PLGA-AB NPs. It is evidenced that FAP-CAR-CM@PLGA-AB NPs directly suppressed the tumor-promoting effect of senescent CAFs. It also exhibits prolonged blood circulation and enhanced tumor accumulation, dual-cleared CAFs and senescent CAFs, improved radiation resistance in both acquired and patient-derived radioresistant tumor cells, and effective antitumor effect with the tumor suppression rate of 86.7%. In addition, FAP-CAR-CM@PLGA-AB NPs reverse the tumor immunosuppressive microenvironment and enhance systemic antitumor immunity. The biomimetic system for dual-targeted clearance of CAFs and senescent CAFs provides a potential strategy for enhancing the radio-sensitization of breast cancer.

Multifunctional Injectable Hydrogel Microparticles Loaded with miR-29a Abundant BMSCs Derived Exosomes Enhanced Bone Regeneration by Regulating Osteogenesis and Angiogenesis.

The study investigated whether both the osteogenic and angiogenic potential of Exos (Exosomes) can be enhanced by overexpression of exosomal miRNA (microRNA) and to confirm whether Exos loaded in HMPs (Hydrogel microparticles) exert long-term effects during new bone formation. BMSCs and Exos are successfully obtained. In vitro and in vivo experiments confirmed that HDAC4 (Histone deacetylase 4) is inhibited by miR-29a overexpression accompanied by the upregulation of RUNX2 (Runt-related transcription factor 2) and VEGF (Vascular Endothelial Growth Factor), thereby enhancing osteogenic and angiogenic capabilities. The HMP@Exo system is synthesized from HB-PEGDA (Hyperbranched Poly Ethylene Glycol Diacrylate)- and SH-HA (Sulfhydryl-Modified Hyaluronic Acid)-containing Exos using a microfluidic technique. The HMP surface is modified with RGD (Arg-Gly-Asp) peptides to enhance cell adhesion. The system demonstrated good injectability, remarkable compatibility, outstanding cell adhesion properties, and slow degradation capacity, and the sustained release of Agomir-29a-Exos (Exosomes derived from Agomir-29a transfected BMSCs) from HMPs enhanced the proliferation and migration of BMSCs and HUVECs (Human Umbilical Vein Endothelial Cells) while promoting osteogenesis and angiogenesis. Overall, the findings demonstrate that the HMP@Exo system can effectively maintain the activity and half-life of Exos, accompanied by overexpression of miR-29a (microRNA-29a). The injectable system provides an innovative approach for accelerating fracture healing by coupling osteogenesis and angiogenesis.

Large detection range and high strain sensitivity fiber SPR sensor based on wave structure.

To achieve a fiber strain sensor with a large detection range and high sensitivity, this paper proposes a wave structured fiber SPR strain sensor. When subjected to axial strain, the wave structured fiber is stretched axially, increasing the stretchability of the sensor and achieving a large detection range strain sensing. Meanwhile, axial strain reduces the longitudinal amplitude of the fiber wave structure, effectively changing the total reflection angle of the transmitted beam at the peak and valley (SPR incidence angle) to achieve high sensitivity SPR strain sensing. The experiment indicates that the strain detection range of the sensor can reach 0-1800µÎµ, with a maximum strain sensitivity of 36.25pm/µÎµ. The wave structured fiber SPR strain sensor designed in this article provides a new approach to improve the range and sensitivity of strain detection.

2 × 4†kW near-single-mode laser output assisted by an optimized bidirectional oscillating-amplifying integrated fiber laser configuration.

Bidirectional output oscillating-amplifying integrated fiber laser (B-OAIFL) can achieve the two-ports laser amplification based on a single cavity, showcasing a promising prospect. In order to improve both the laser power and beam quality, we first simulate and optimize the stimulated Raman scattering (SRS) effect in the B-OAIFL. The simulation results show the SRS effect can be suppressed by optimizing the diameter as well as the length of the active fiber at different locations. With the guidance of theoretical and experimental analysis for the combined suppression of SRS and transverse mode instability (TMI), a near-single-mode B-OAIFL with 2 × 4 kW was demonstrated. Based on this foundation, we further devoted ourselves to the pursuit of the optimization of the structure and performance. The necessity of the configuration of side pump, which was initially introduced for its exceptional performance in stabilizing temporal chaos, was reevaluated in detail. With its negative impacts on efficiency improvement and SRS suppression were analyzed and verified, we removed this configuration and finally demonstrated a more simplified design with superior performance. A total bidirectional output of 8105 W was achieved, with an O-O efficiency of 79.6% and a near-single-mode beam quality of M A 2∼1.36,M B 2∼1.63. No signs of TMI were observed, and the signal-to-SRS suppression ratio was over 38 dB. The results still demonstrate a promising potential for power scaling based on this configuration and parameters.

Spiral cone fiber SPR sensor for detecting ginsenoside Rg1.

The conical fiber SPR sensor is easy to manufacture and has been used in biochemical detection research, but it has the problem of structural fragility. This article proposes a spiral cone fiber SPR sensor, which introduces a spiral structure on the 76µm fiber coarse cone, achieving good coupling of the core mode into the cladding mode, and improving the physical strength and practicality of the cone-shaped fiber SPR sensor. By modifying the target protein on the surface of the sensor gold film, specific detection of ginsenoside Rg1, an active ingredient of traditional Chinese medicine ginseng, was achieved. The detection sensitivity was 0.138 nm/(µm/ml) and the detection limit was 0.22µm/ml. The proposed spiral cone fiber SPR sensor provides a new scheme for the specific detection of active ingredients in traditional Chinese medicine, which is structurally stable and physically strong.

High sensitivity fiber SPR sensor based on a spiral coarse cone structure.

A fiber SPR sensor can achieve rapid and portable detection of trivalent arsenic ions (As3+) in drinking water or food, but their sensitivity and detection limit need to be further improved and developed toward specific detection. This article proposed the implementation of the SPR sensor using a biased core fiber spiral coarse cone structure. The fine core of the biased core fiber was used to reduce the mode of transmitted light. By controlling the pitch of the spiral core to control the SPR incidence angle, a significant increase in the sensitivity of the fiber SPR sensor was achieved. Meanwhile, the harmless glutathione (GSH) was modified on the surface of the sensing gold film to achieve the specific detection of As3+. The experimental results indicate that the spiral coarse cone fiber SPR sensor proposed in this article has a detection sensitivity of 32.48 nm/ppb for As3+, with a detection limit as low as 0.011 ppb, meeting the detection requirements of the World Health Organization for As3+ in water, which provides a new feasible solution for fast, portable, and highly sensitive detection of metal ions in water and food.

Activation of moderate autophagy promotes survival of fat graft.

Clinically unpredictable retention following fat grafting remains outstanding problems because of the unrevealed mechanism of grafted fat survival. The role of autophagy, a process to maintain cellular homeostasis through recycling cellular debris, has yet been to be reported in fat grafting. This study aims to improve the survival of fat grafting through the autophagy. First, the relationship between cell death and autophagy in the early stage of fat grafting was evaluated through immunostaining, RNA sequencing, and western blot. Next, rapamycin, an autophagic agonist, was used for the culturing of adipose-derived stem cells and adipocytes during ischemia. Cell death, autophagy, and reactive oxygen species (ROS) were assayed. Finally, rapamycin was used to assist fat grafting in nude mice. The results demonstrated that the peak of cell death at the early stage of fat grafting was accompanied by a decrease in autophagy. In vitro, during ischemia, 25 nM was confirmed as the optimal dose of rapamycin that reduces cell death with enhanced autophagy and mitophagy, improved mitochondrial quality as well as decreased ROS accumulation. In vivo, promoted mitophagy, alleviated oxidative stress, and decreased cell apoptosis of rapamycin-treated fat grafts were observed in the early stage. In addition, rapamycin increased the survival of fat grafts with increased neovascularization and reduced fibrosis. We suggested that moderate autophagy induced by rapamycin contribute to enhanced ischemic tolerance and long term survival of fat grafts through mitochondrial quality control.

Treg-Derived Extracellular Vesicles: Roles in Diseases and Theranostics.

Regulatory T cells (Tregs), a subset of CD4+ T cells, are indispensable in maintaining immune self-tolerance and have been utilized in various diseases. Treg-derived extracellular vesicles (Treg-EVs) have been discovered to play an important role in the mechanism of Treg functions. As cell-derived membranous particles, EVs carry multiple bioactive substances that possess tremendous potential for theranostics. Treg-EVs are involved in numerous physiological and pathological processes, carrying proteins and miRNAs inherited from the parental cells. To comprehensively understand the function of Treg-EVs, here we reviewed the classification of Treg-EVs, the active molecules in Treg-EVs, their various applications in diseases, and the existing challenges for Treg-EVs based theranostics. This Review aims to clarify the feasibility and potential of Treg-EVs in diseases and theranostics, facilitating further research and application of Treg-EVs.

Hypertension associated with niraparib in cancer patients: A pharmacovigilance analysis based on the FAERS database and meta-analysis of randomized controlled trials.

BACKGROUND: Niraparib plays a crucial role in the treatment of ovarian cancer. A comprehensive understanding of the incidence and risk of hypertension associated with niraparib would be of vital importance to healthcare practitioners. METHODS: In this study, an observational, retrospective, pharmacovigilance study was conducted based on the FDA Adverse Event Reporting System (FAERS) database. Cases of hypertension related to niraparib were extracted for disproportionality analysis from the first quarter (Q1) of 2017 to Q1 of 2023. Moreover, a separate meta-analysis was performed using the randomized controlled trials (RCTs) on niraparib for cancer treatment published in PubMed, Embase, and Web of Science from inception to May 31st, 2023. The primary outcomes were the incidence and risk of hypertension associated with niraparib. RESULTS: In the FAERS, 1196 hypertension cases were found to be related to niraparib treatment. Notably, niraparib exhibited the highest level of disproportionality, as indicated by a reporting odds ratio (ROR) of 2.85 (95% CI, 2.69-3.01), suggesting a greater likelihood of causing hypertension compared to other poly-ADP-ribose polymerase (PARP) inhibitors (P < 0.01). Our safety meta-analysis included five pivotal RCTs of niraparib that reported hypertension. In comparison to placebo treatment, the meta-analysis demonstrated a significant increase in the risk of hypertension with niraparib (OR 2.84 [95% CI, 2.17-3.72], P < 0.01), with no heterogeneity observed among the studies (I2 = 0%, χ2 = 2.02, P = 0.73). The incidence of niraparib-induced hypertension was determined to be 16.9% (95% CI, 14.9-18.9; I2 = 34%). CONCLUSIONS: These findings suggest that hypertension is a distinctive adverse event associated with niraparib compared to other PARP inhibitors. Niraparib significantly increases the risk of hypertension that needs early recognition and management in clinical medication.

Lipocalin 2 (LCN2) confers acquired resistance to almonertinib in NSCLC through LCN2-MMP-9 signaling pathway.

Almonertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is highly selective for EGFR-activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC). However, the development of resistance inevitably occurs and poses a major obstacle to the clinical efficacy of almonertinib. Therefore, a clear understanding of the mechanism is of great significance to overcome drug resistance to almonertinib in the future. In this study, NCI-H1975 cell lines resistant to almonertinib (NCI-H1975 AR) were developed by concentration-increasing induction and were employed for clarification of underlying mechanisms of acquired resistance. Through RNA-seq analysis, the HIF-1 and TGF-ß signaling pathways were significantly enriched by gene set enrichment analysis. Lipocalin-2 (LCN2), as the core node in these two signaling pathways, were found to be positively correlated to almonertinib-resistance in NSCLC cells. The function of LCN2 in the drug resistance of almonertinib was investigated through knockdown and overexpression assays in vitro and in vivo. Moreover, matrix metalloproteinases-9 (MMP-9) was further identified as a critical downstream effector of LCN2 signaling, which is regulated via the LCN2-MMP-9 axis. Pharmacological inhibition of MMP-9 could overcome resistance to almonertinib, as evidenced in both in vitro and in vivo models. Our findings suggest that LCN2 was a crucial regulator for conferring almonertinib-resistance in NSCLC and demonstrate the potential utility of targeting the LCN2-MMP-9 axis for clinical treatment of almonertinib-resistant lung adenocarcinoma.

Distribution characteristics of sulfonamide antibiotics between water and extracellular polymeric substances in municipal sludge.

The interaction between extracellular polymeric substances (EPS) in municipal sludge and antibiotics in wastewater is critical in wastewater treatment, resource recovery, and sludge management. Therefore, it is increasingly urgent to investigate the distribution coefficient (Log K) of sulfonamide antibiotics (SAs) in EPS, particularly in sludge-derived dissolved organic carbon (DOC) and aqueous phase systems. Herein, through balance experiments, the concentrations of SAs were determined using alkaline extraction EPS (AEPS) and alginate-like extracellular polymer (ALE) systems, and the Log KDOC values were determined. The results showed that the Log KDOC of AEPS was higher than that of ALE, which exhibited a negative KDOC value, indicating an inhibitory effect on dissolution. For the three SAs studied, the Log KDOC values were in the following order: sulfamethoxazole > sulfapyridine > sulfadiazine. This order can be attributed to the differing physicochemical properties, such as polarity, of the SAs. Three-dimensional excitation-emission matrix fluorescence spectra and fitting results indicated a lack of aromatic proteins dominated by tryptophan and humus-like substances in ALE. Meanwhile, the hydrophobic interaction of aromatic proteins dominated by tryptophan was the main driving force in the binding process between AEPS and SAs.

Application of Indian ink markers for locating gastric varices under endoscopic ultrasonography.

OBJECTIVE: The present study aimed to investigate the accuracy of endoscopic ultrasonography (EUS) combined with Indian ink in locating target vessels of gastric varices (GVs) compared with conventional endoscopic techniques. Additionally, the characteristics of GVs under conventional endoscopy were also explored. METHODS: All 50 cirrhotic patients with GVs between August 2021 and December 2022 were included in the study. Firstly, conventional endoscopy was employed to identify GVs and to record the expected injection sites. Subsequently, EUS was used to locate the perforated vessel and the injection site was them marked with India ink followed by injection with cyanoacrylate (CYA). Finally, conventional endoscopy was used to examine GVs, to identify the marker points of Indian ink and to compare whether the injection points under conventional endoscopy were consistent with those marked with Indian ink. Furthermore, patients with consistent and inconsistent distribution of endoscopic markers and injection sites were divided into two groups. RESULTS: EUS could detect the perforating vessels in real time and intuitively. The distribution of markers using EUS was significantly different compared with the injection points obtained by conventional endoscopy (P < 0.001). Therefore, 20 cases were allocated to the consistent group and 30 cases to the non-consistent group. 16 patients who showed red wale signs were obtained in the consistent group and 11 patients in the non-consistent group (P = 0.048). The diameter of the largest GVs was 13.5 (10-15) mm in the consistent group compared with 10 (7.5-10) mm in the non-consistent group (P = 0.006). CONCLUSION: EUS could provide the exact location of GVs, thus more accurately describing the endoscopic characteristics of the GVs. Furthermore, the red wale signs and diameter of the largest GVs obtained using conventional endoscopy were helpful in determining the location of target GVs.

Evolutionary shifts in pheromone receptors contribute to speciation in four Helicoverpa species.

Male moths utilize their pheromone communication systems to distinguish potential mates from other sympatric species, which contributes to maintaining reproductive isolation and even drives speciation. The molecular mechanisms underlying the evolution of pheromone communication systems are usually studied between closely-related moth species for their similar but divergent traits associated with pheromone production, detection, and/or processing. In this study, we first identified the functional differentiation in two orthologous pheromone receptors, OR14b, and OR16, in four Helicoverpa species, Helicoverpa armigera, H. assulta, H. zea, and H. gelotopoeon. To understand the substrate response specificity of these two PRs, we performed all-atom molecular dynamics simulations of OR14b and OR16 based on AlphaFold2 structural prediction, and molecular docking, allowing us to predict a few key amino acids involved in substrate binding. These candidate residues were further tested and validated by site-directed mutagenesis and functional analysis. These results together identified two hydrophobic amino acids at positions 164 and 232 are the determinants of the response specificity of HarmOR14b and HzeaOR14b to Z9-14:Ald and Z9-16:Ald by directly interacting with the substrates. Interestingly, in OR16 orthologs, we found that position 66 alone determines the specific binding of Z11-16:OH, likely via allosteric interactions. Overall, we have developed an effective integrated method to identify the critical residues for substrate selectivity of ORs and elucidated the molecular mechanism of the diversification of pheromone recognition systems.

A novel correction method for modelling parameter-driven autocorrelated time series with count outcome.

BACKGROUND: Count time series (e.g., daily deaths) are a very common type of data in environmental health research. The series is generally autocorrelated, while the widely used generalized linear model is based on the assumption of independent outcomes. None of the existing methods for modelling parameter-driven count time series can obtain consistent and reliable standard error of parameter estimates, causing potential inflation of type I error rate. METHODS: We proposed a new maximum significant ρ correction (MSRC) method that utilizes information of significant autocorrelation coefficient ρ estimate within 5 orders by moment estimation. A Monte Carlo simulation was conducted to evaluate and compare the finite sample performance of the MSRC and classical unbiased correction (UB-corrected) method. We demonstrated a real-data analysis for assessing the effect of drunk driving regulations on the incidence of road traffic injuries (RTIs) using MSRC in Shenzhen, China. Moreover, there is no previous paper assessing the time-varying intervention effect and considering autocorrelation based on daily data of RTIs. RESULTS: Both methods had a small bias in the regression coefficients. The autocorrelation coefficient estimated by UB-corrected is slightly underestimated at high autocorrelation (≥ 0.6), leading to the inflation of the type I error rate. The new method well controlled the type I error rate when the sample size reached 340. Moreover, the power of MSRC increased with increasing sample size and effect size and decreasing nuisance parameters, and it approached UB-corrected when ρ was small (≤ 0.4), but became more reliable as autocorrelation increased further. The daily data of RTIs exhibited significant autocorrelation after controlling for potential confounding, and therefore the MSRC was preferable to the UB-corrected. The intervention contributed to a decrease in the incidence of RTIs by 8.34% (95% CI, -5.69-20.51%), 45.07% (95% CI, 25.86-59.30%) and 42.94% (95% CI, 9.56-64.00%) at 1, 3 and 5 years after the implementation of the intervention, respectively. CONCLUSIONS: The proposed MSRC method provides a reliable and consistent approach for modelling parameter-driven time series with autocorrelated count data. It offers improved estimation compared to existing methods. The strict drunk driving regulations can reduce the risk of RTIs.

Prevalence and genotype/subtype distribution of Enterocytozoon bieneusi and Blastocystis in donkeys in Shanxi Province, north China.

Enterocytozoon bieneusi and Blastocystis may cause diarrhea in humans and various animals. However, little information is available regarding the prevalence and genetic diversity of E. bieneusi and Blastocystis in donkeys. To fill this gap, we molecularly assessed E. bieneusi and Blastocystis in fecal samples from donkeys (n = 815) in Shanxi Province, north China. The overall prevalence of E. bieneusi and Blastocystis in donkeys was 8.1% and 0.2%, respectively. Region and age were risk factors associated with E. bieneusi infection in donkeys. Three internal transcribed spacer (ITS) genotypes of E. bieneusi were identified in the current study, including two previously described genotypes (D and Henan-IV) and one novel genotype (named SXD1). Of which, genotype D was found to be the most prevalent. Phylogenetic analysis demonstrated that the three genotypes belonged to group 1, implying a potential of zoonotic transmission. Multilocus sequence typing showed that 19, 15, 13, and 22 types were identified at the loci MS1, MS3, MS4, and MS7, respectively, forming six multilocus genotypes (MLGs) distributed in the genotype D. One Blastocystis subtype (ST33) was identified, which has previously been reported only in horses. This is the first molecular-based description of E. bieneusi and Blastocystis infections in donkeys in Shanxi Province, north China, contributing to a better understanding of transmission dynamics and molecular epidemiological characteristics of the two intestinal protozoa.

Blocking Gremlin1 inhibits M1 macrophage polarization through Notch1/Hes1 signaling pathway in apical periodontitis.

BACKGROUND: Gremlin1 is a multifunctional protein whose expression is demonstrated to be involved in a series of physiology and pathological processes. The association between Gremlin1 and apcial periodontitis (AP) has been established. M1-polarized macrophages are crucial immune cells that exacerbate the progression of apical periodontal inflammatory response, but the function of Gremlin1 during macrophages activation in periapical lesions is still unclear. This study attempts to explore the regulatory effects of Gremlin1 on macrophage polarization on apical periodontitis microenviroment. METHODS: Clinical specimens were used to determine the expression of Gremlin1 in periapical tissues by immunohistochemical (IHC) staining. Then, the disease models of periapical inflammation in rats were established, and adenovirus- associated virus (AAVs) was used to blockade Gremlin1 expression. Lentivirus carrying sh-Gremlin1 particles were used to transfect THP-1 induced M1-subtype macrophages. To assess the expression of associated molecules, Western-blot, immunofluorescence staining were performed. RESULTS: Gremlin1 was significantly up-regulated in the periapical tissues of subjects with AP as identified by IHC staining, and positively correlated with levels of M1 macrophage-associated genes. Rats AP model with inhibition of Gremlin1 in periapical lesions exhibited limited infiltration of macrophages and decreased expression of M1 macrophage-related genes in periapical lesions. Furthermore, Gremlin1 blockade substantially decreased the Notch1/Hes1 signaling pathway activation level. The in vitro experiments confirmed the above results. CONCLUSION: Taken together, current study illustrated that the Gremlin1 suppression in periapical lesions inhibited M1 macrophage polarization through Notch1/Hes1 axis. Moreover, Gremlin1 may act as a potential candidate in the treatment of AP.

Interpretable baseflow segmentation and prediction based on numerical experiments and deep learning.

Baseflow is a crucial water source in the inland river basins of high-cold mountainous region, playing a significant role in maintaining runoff stability. It is challenging to select the most suitable baseflow separation method in data-scarce high-cold mountainous region and to evaluate effects of climate factors and underlying surface changes on baseflow variability and seasonal distribution characteristics. Here we attempt to address how meteorological factors and underlying surface changes affect baseflow using the Grey Wolf Optimizer Digital Filter Method (GWO-DFM) for rapid baseflow separation and the Long Short-Term Memory (LSTM) neural network model for baseflow prediction, clarifying interpretability of the LSTM model in baseflow forecasting. The proposed method was successfully implemented using a 63-year time series (1958-2020) of flow data from the Tai Lan River (TLR) basin in the high-cold mountainous region, along with 21 years of ERA5-land meteorological data and MODIS data (2000-2020). The results indicate that: (1) GWO-DFM can rapidly identify the optimal filtering parameters. It employs the arithmetic average of three methods, namely Chapman, Chapman-Maxwell and Eckhardt filter, as the best baseflow separation approach for the TLR basin. Additionally, the baseflow significantly increases after the second mutation of the baseflow rate. (2) Baseflow sources are mainly influenced by precipitation infiltration, glacier frozen soil layers, and seasonal ponding. (3) Solar radiation, temperature, precipitation, and NDVI are the primary factors influencing baseflow changes, with Nash-Sutcliffe efficiency coefficients exceeding 0.78 in both the LSTM model training and prediction periods. (4) Changes in baseflow are most influenced by solar radiation, temperature, and NDVI. This study systematically analyzes the changes in baseflow and response mechanisms in high-cold mountainous region, contributing to the management of water resources in mountainous basins under changing environmental conditions.