METTL14 plays an oncogenic role in NSCLC by modulating ferroptosis and the m6A modification of GPX4.

CONTEXT: N6-methyladenosine (m6A) of RNA is involved in the progression of non-small cell lung cancer (NSCLC). OBJECTIVE: This study investigated the role of METTL14 in NSCLC and the mechanism. MATERIALS AND METHODS: Expression levels were assessed by quantitative real-time PCR and ELISA assays. Cells viability was assessed by cell counting kit-8. M6A methylation was analysed by methylated RNA immunoprecipitation (MeRIP), RIP, luciferase assay, and mRNA stability assay. RESULTS: The results showed that METTL14 was highly expressed in NSCLC tissues and cell lines. Knockdown of METTL14 inhibited the cell viability while induced ferroptosis of NSCLC cells. Mechanistically, METTL14 interacts with GPX4, mediates m6A modification of GPX4, enhances its mRNA stability, and upregulates its expression. In addition, IGF2BP1 recognises the m6A-methylated GPX4 and mediates the elevated mRNA stability. Moreover, GPX4 reversed the effects of METTL14 depletion. DISCUSSION AND CONCLUSION: The METTL14/GPX4 axis promotes NSCLC progression by inhibiting cell ferroptosis through the recognition of m6A modification mediated by IGF2BP1.

Knockdown of miR-1293 attenuates lung adenocarcinoma angiogenesis via Spry4 upregulation-mediated ERK1/2 signaling inhibition.

Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Angiogenesis plays a pivotal role in LUAD progression via supplying oxygen and nutrients for cancer cells. Non-coding miR-1293, a significantly up-regulated miRNA in LUAD tissues, can be potentially used as a novel biomarker for predicting the prognosis of LUAD patients. However, little information is available about the function of miR-1293 in LUAD progression especially cancer-induced angiogenesis. Herein, we found that miR-1293 knockdown could obviously attenuate LUAD-induced angiogenesis in vitro and down-regulate two most important pro-angiogenic cytokines VEGF-A and bFGF expression and secretion. Indeed, miR-1293 abrogation inactivated the angiogenesis-promoting ERK1/2 signaling characterized by decreased ERK1/2 phosphorylation and translocation from nucleus to cytoplasm. Next we found that miR-1293 knockdown reactivated the endogenous ERK1/2 pathway inhibitor Spry4 expression and Spry4 perturbance with specific siRNA transfection abolished the inhibition of ERK1/2 pathway and LUAD-induced angiogenesis by miR-1293 knockdown. Finally, with in vivo assay, we found obvious Spry4 up-regulation and VEGF-A, bFGF, ERK1/2 phosphorylation, micro-vessel density marker CD31 expression down-regulation in vivo, respectively. Collectively, these results indicated that miR-1293 knockdown could significantly attenuate LUAD angiogenesis via Spry4-mediated ERK1/2 signaling inhibition, which might be helpful for uncovering more functions of miR-1293 in LUAD and providing experimental basis for possible LUAD therapeutic strategy targeting miR-1293.

Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer.

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

Nano molybdenum trioxide-mediated enhancement of soybean yield through improvement of rhizosphere soil molybdenum bioavailability for nitrogen-fixing microbial recruitment.

Molybdenum (Mo) plays a pivotal role in the growth and nitrogen-fixing process of plants mediated by rhizobia. However, the influence of nano­molybdenum trioxide (MoO3NPs) on soybean growth, rhizosphere bioavailable Mo, and nitrogen-fixing microorganisms remains underexplored. Here, we report that compared with that of ionic Mo and bulk MoO3, the utilization of MoO3NPs (specifically NPs0.05 and NPs0.15) significantly boosted the available Mo content in the rhizosphere soil throughout the seedling (by 21.64 %-101.38 %), podding (by 54.44 %-68.89 %), and mature stage (by 34.41 %-to 45.71 %) of soybean growth. Furthermore, both NPs0.05 and NPs0.15 treatments maintained consistently higher levels of acid-extractable Mo, reducible Mo, and oxidizable Mo across these stages, which facilitated stable conversion and supply of bioavailable Mo. Within the rhizosphere soil, NPs0.05 and NPs0.15 treatments resulted in the highest relative abundance of Rhizobiales and Bradyrhizobium genera, and significantly promoted the colonization of nitrogen-fixing microorganisms, thereby increasing the content of nitrate nitrogen (NO3--N) by 8.69 % and 7.72 % and ammonium nitrogen (NH4+-N) by 44.75 % and 17.55 %, respectively. Ultimately, these effects together contributed to 107.17 % and 84.00 % increment in soybean yield by NPs0.05 and NPs0.15 treatments, respectively. In summary, our findings underscore the potential of employing MoO3NPs to promote plant growth and maintain soil nitrogen cycling, indicating distinct advantages of MoO3NPs over ionic Mo and bulk MoO3.

The single cell immunogenomic landscape after neoadjuvant immunotherapy combined chemotherapy in esophageal squamous cell carcinoma.

Neoadjuvant immunotherapy represents promising strategy in the treatment of esophageal squamous cell carcinoma (ESCC). However, the mechanisms underlying its impact on treatment sensitivity or resistance remain a subject of controversy. In this study, we conducted single-cell RNA and T/B cell receptor (scTCR/scBCR) sequencing of CD45+ immune cells on samples from 10 patients who received neoadjuvant immunotherapy and chemotherapy. We also validated our findings using multiplexed immunofluorescence and analyzed bulk RNA-seq from other cohorts in public database. By integrating analysis of 87357 CD45+ cells, we found GZMK + effector memory T cells (Tem) were relatively enriched and CXCL13+ exhausted T cells (Tex) and regulator T cells (Treg) decreased among responders, indicating a persistent anti-tumor memory process. Additionally, the enhanced presence of BCR expansion and somatic hypermutation process within TNFRSF13B + memory B cells (Bmem) suggested their roles in antigen presentation. This was further corroborated by the evidence of the T-B co-stimulation pattern and CXCL13-CXCR5 axis. The complexity of myeloid cell heterogeneity was also particularly pronounced. The elevated expression of S100A7 in ESCC, as detected by bulk RNA-seq, was associated with an exhausted and immunosuppressive tumor microenvironment. In summary, this study has unveiled a potential regulatory network among immune cells and the clonal dynamics of their functions, and the mechanisms of exhaustion and memory conversion between GZMK + Tem and TNFRSF13B + Bmem from antigen presentation and co-stimulation perspectives during neoadjuvant PD-1 blockade treatment in ESCC.

Glycoursodeoxycholic Acid Alleviates Arterial Thrombosis via Suppressing Diacylglycerol Kinases Activity in Platelet.

BACKGROUND: Glycoursodeoxycholic acid (GUDCA) has been acknowledged for its ability to regulate lipid homeostasis and provide benefits for various metabolic disorders. However, the impact of GUDCA on arterial thrombotic events remains unexplored. The objective of this study is to examine the effects of GUDCA on thrombogenesis and elucidate its underlying mechanisms. METHODS: Plasma samples from patients with arterial thrombotic events and diet-induced obese mice were collected to determine the GUDCA concentrations using mass spectrometry. Multiple in vivo murine thrombosis models and in vitro platelet functional assays were conducted to comprehensively evaluate the antithrombotic effects of GUDCA. Moreover, lipidomic analysis was performed to identify the alterations of intraplatelet lipid components following GUDCA treatment. RESULTS: Plasma GUDCA level was significantly decreased in patients with arterial thrombotic events and negatively correlated with thrombotic propensity in diet-induced obese mice. GUDCA exhibited prominent suppressing effects on platelet reactivity as evidenced by the attenuation of platelet activation, secretion, aggregation, spreading, and retraction (P<0.05). In vivo, GUDCA administration robustly alleviated thrombogenesis (P<0.05) without affecting hemostasis. Mechanistically, GUDCA inhibited DGK (diacylglycerol kinase) activity, leading to the downregulation of the phosphatidic acid-mediated signaling pathway. Conversely, phosphatidic acid supplementation was sufficient to abolish the antithrombotic effects of GUDCA. More importantly, long-term oral administration of GUDCA normalized the enhanced DGK activity, thereby remarkably alleviating the platelet hyperreactivity as well as the heightened thrombotic tendency in diet-induced obese mice (P<0.05). CONCLUSIONS: Our study implicated that GUDCA reduces platelet hyperreactivity and improves thrombotic propensity by inhibiting DGKs activity, which is a potentially effective prophylactic approach and promising therapeutic agent for arterial thrombotic events.

Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2ß1.

Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

Clinical characteristics and therapeutic strategy for patients with spontaneous isolated abdominal aortic dissection.

Objective: Spontaneous isolated abdominal aortic dissection (SIAAD) is a rare aortic emergency and not yet fully understood. This study aims to report the characteristics and treatments of 31 patients with SIAAD in the past 12 years. Methods: A total of 31 consecutive patients with SIAAD between 2010 and 2022 were included. The clinical manifestations, treatment strategies, and outcomes were reviewed. Following the SVS/STS reporting standard, we compared the clinical characteristics with different locations of primary entry, or different numbers of dissected zones. Furthermore, we compared the effects of surgical and conservative therapies on the outcome during the follow-up. Results: Among the 31 patients with SIAAD, 16 (51.6%) were in the acute phase on admission. The primary entry of SIAAD was mainly located in Zone 9 (67.7%). Most patient presented with dissection involving 1 or 2 aortic zones (61.3%). In addition, 35.5% and 64.5% of SIAADs involved the visceral and iliac arteries, respectively. Compared with asymptomatic SIAADs, the symptomatic ones had longer dissection lengths (P = 0.008) and tended to involve iliac artery more frequently (P = 0.098). There were differences in the number of dissected aortic zones (P = 0.005) among patients with primary entry located in Zone 5 (Supraceliac aorta), Zone 6-8 (Paravisceral aorta) and Zone 9 (Infrarenal aorta). The involvement of visceral artery (P = 0.039) and iliac artery (P = 0.006) was significantly different between the subgroups of SIAAD involving one, two, and three or more aortic zones. The cumulative incidence of adverse false lumen progression events was significantly lower (P = 0.000) and the rate of false lumen thrombogenesis or disappearance was higher in patients receiving surgery (P = 0.001). The cumulative all-cause mortality was 9.7% at 1-year, and 19.7% at 5-year, with no significant difference between surgical and conservative therapies. Conclusions: Clinical features of SIAAD vary depending on the location of the primary entry and the number of dissected aortic zones. Although surgery was not associated with a lower all-cause mortality compared with conservative therapy, it was associated with a lower incidence of adverse false lumen progression and a higher rate of aortic remodeling.

Atmospheric mercury in a developed region of eastern China: Interannual variation and gas-particle partitioning.

Atmospheric mercury plays a crucial role in the biogeochemical cycle of mercury. This study conducted an intensive measurement of atmospheric mercury from 2015 to 2018 at a regional site in eastern China. During this period, the concentration of particle-bound mercury (PBM) decreased by 13%, which was much lower than those of gaseous elemenral mercury (GEM, 30%) and reactive gaseous mercury (GOM, 62%). The gradual decrease in the correlation between PBM and CO, K, and Pb indicates that the influence of primary emissions on PBM concentration was weakening. Moreover, the value of the partitioning coefficient (Kp) increased gradually from 0.05 ± 0.076 m3/µg in 2015 to 0.16 ± 0.37 m3/µg in 2018, indicating that GOM was increasingly inclined to adsorb onto particulate matter. Excluding the influence of meteorological conditions and the primary emissions, the change in aerosol composition is designated as the main trigger factor for the increasing gas-particle partitioning of reactive mercury (RM). The increasing ratio of Cl-, NO3-, and organics (Org) in the chemical composition of particle matters (PM2.5), as well as the decrease in the proportion of SO42-, NH4+, and K+, are conducive to the adsorption of GOM onto particles, forming PBM, which led to an increase of Kp and a lag of PBM reduction compared to GEM and GOM under the continuous control measures of anthropogenic mercury emissions. The evolution of aerosol compositions in recent years affects the migration and transformation of atmospheric mercury, which in turn can affect the biogeochemical cycle of mercury.

"Dominolike" Barriers Elimination with an Intratumoral Adenosine-Triphosphate-Supersensitive Nanogel to Enhance Cancer Chemoimmunotherapy.

Pathophysiological barriers in "cold" tumors seriously limit the clinical outcomes of chemoimmunotherapy. These barriers distribute in a spatial order in tumors, including immunosuppressive microenvironment, overexpressed chemokine receptors, and dense tumor mesenchyme, which require a sequential elimination in therapeutics. Herein, we reported a "dominolike" barriers elimination strategy by an intratumoral ATP supersensitive nanogel (denoted as BBLZ-945@PAC-PTX) for enhanced chemoimmunotherapy. Once it has reached the tumor site, BBLZ-945@PAC-PTX nanogel undergoes supersensitive collapse triggered by adenosine triphosphate (ATP) in perivascular regions and releases BLZ-945 conjugated albumin (BBLZ-945) to deplete tumor-associated macrophages (TAMs). Deeper spatial penetration of shrunk nanogel (PAC-PTX) could not only block CXCR4 on the cell membrane to decrease immunosuppressive cell recruitment but also internalize into tumor cells for tumor-killing and T cell priming. The strategy of "dominolike" barriers elimination in tumors enables immune cell infiltration for a potentiated immune response and offers a high-responsive treatment opinion for chemoimmunotherapy.

Atmospheric saccharides over the East China Sea: Assessment of the contribution of sea-land emission and the aging of levoglucosan.

A one-year observation of aerosols on a remote island was conducted and saccharides were applied to reveal the behaviors of organic aerosol in the East China Sea (ECS). The seasonal fluctuations of total saccharides were relatively small, with annual mean concentration of 64.82 ± 26.88 ng/m3, contributing 10.20 % and 4.90 % to WSOC and OC, respectively. However, the individual species showed significant seasonal variations due to the differences in both the emission sources and the influencing factors between marine and terrestrial areas. Anhydrosugars was the highest species and showed little diurnal variation in air mass from land areas. Primary sugars and primary sugar alcohols showed higher concentrations in blooming spring and summer and were higher in daytime than nighttime due to intense biogenic emissions both in marine and mainland areas. Accordingly, secondary sugar alcohols showed obvious different diurnal variation with ratios of day/night reducing to 0.86 in summer but even increasing to 1.53 in winter, attributing to the additional impact of secondary transmission process. Source appointment suggested that biomass burning emission (36.41 %) and biogenic emission (43.17 %) were the main causes of organic aerosol, while anthropogenic related secondary process and sea salt injection accounted for 13.57 % and 6.85 %, respectively. We further elucidate that the biomass burning emission might be underestimated, as levoglucosan undergoes degradation processes in the atmosphere, which are affected by various atmospheric physicochemical factors, and the degradation degree is particularly severe in remote areas like the oceans. In addition, significantly low ratio of levoglucosan to mannosan (L/M) occurred in air mass from marine area, indicating that levoglucosan was likely be more fully aged after hovering over a large-scale of oceanic area.

The role of phosphorus speciation of biochar in reducing available Cd and phytoavailability in mining area soil: Effect and mechanism.

The effect of phosphorus (P) speciation in biochar on soil available Cd and its mechanism to alleviate plant Cd stress remain largely unknown. Here, ammonium polyphosphate (PABC)-, phosphoric acid (PHBC)-, potassium dihydrogen phosphate (PKBC)-, and ammonium dihydrogen phosphate (PNBC)-modified biochar were used to investigate P speciation. The Cd immobilization mechanism of biochar was analyzed by XPS and 31P NMR, and the soil quality and the mechanism for the biochar to alleviate Cd stress were also determined. The results demonstrated that PBC (pristine biochar), PABC, PHBC, PKBC, and PNBC reduced the content of soil DTPA-Cd by 14.96 % - 32.19 %, 40.44 % - 47.26 %, 17.52 % - 41.78 %, and 21.90 % - 36.64 %, respectively. The XPS and 31P NMR results demonstrated that the orthophosphate on the surface of PABC, PHBC, PKBC, and PNBC accounted for 82.06 %, 62.77 %, 33.1 %, and 54.46 %, respectively, indicating that PABC has the highest passivation efficiency on soil Cd, which was ascribed to the highest orthophosphate content on the biochar surface. Pot experiments revealed that PABC could reduce the Cd content by 4.18, 4.41, 4.43, 2.94, and 2.57 folds in roots, stems, leaves, pods, and grains, respectively, and at the same time increase the dry and fresh weight of soybean and decrease Cd toxicity to soybean by improving the antioxidant system. In addition, application of the P-modified biochars improved the enzyme activity and physicochemical properties of the soil. This study provides a new perspective for studying the effect of P-modified biochars on soil Cd immobilization.

Gut Microbiome-Generated Phenylacetylglutamine from Dietary Protein is Associated with Crohn's Disease and Exacerbates Colitis in Mouse Model Possibly via Platelet Activation.

OBJECTIVES: Our aims were to better understand the interplay of diet and gut microbiota in Crohn's disease [CD], taking advantage of a new-onset treatment-naïve CD cohort. We focus on phenylacetylglutamine [PAGln], a diet-derived meta-organismal prothrombotic metabolite. DESIGN: We collected faecal and serum samples from a CD cohort [n = 136] and healthy controls [n = 126] prior to treatment, and quantified serum PAGln using LC-MS/MS. Diet was assessed using food-frequency questionnaires. Mice [C57BL/6] were fed high/low-protein diets and administered dextran sodium sulphate [DSS] to examine plasma PAGly, thrombosis potential, and colitis severity. PAGly or saline was administered to DSS-induced colitis mice, and colitis severity and colonic tissue gene expression were examined. P-selectin and CD40L expression were determined in human platelet-rich plasma [n = 5-6] after exposure to platelet agonists following PAGln priming. Bioinformatic analysis and bacterial culturing identified the main contributor of PAGln in CD. RESULTS: PAGln, a meta-organismal prothrombotic metabolite, is associated with CD. Administration of PAGly exacerbated colitis in a mouse model and upregulated coagulation-related biological processes. Antiplatelet medicine, dipyridamole, attenuated PAGly-enhanced colitis susceptibility. PAGln enhanced platelet activation and CD40L expression in platelet-rich plasma ex vivo. Further study revealed that high dietary protein intake and increased abundance of phenylacetic acid [PAA]-producing Proteobacteria mediated by phenylpyruvate decarboxylase act in concert to cause the elevated PAGln levels in CD patients. CONCLUSION: Taken together, ppdc-carrying Proteobacteria-generated PAGln from dietary protein is associated with CD and exacerbates colitis possibly via platelet-induced coagulation and inflammation These results suggest that PAGln is a potential early diagnostic marker and therapeutic target of CD.

A-RetinaNet: A novel RetinaNet with an asymmetric attention fusion mechanism for dim and small drone detection in infrared images.

To solve the problems of texture lacking and resolution coarseness in the detection of dim and small drone targets in infrared images, we propose a novel RetinaNet with an asymmetric attention fusion mechanism for dim and small drone detection. First, we propose a super-resolution texture-enhancement network as an effective solution for the lack of texture-related information on small infrared targets. The network generates super-resolution images and enhances the texture features of the targets. Second, considering the inadequacy of feature pyramids in the feature fusion stage, we use an asymmetric attention fusion mechanism to constitute an asymmetric attention fusion pyramid network for cross-layer feature fusion in a bidirectional manner; it achieves high-quality semantic and location detail information interaction between scale features. Third, a global average pooling layer is employed to capture global spatial-sensitive information, thus effectively identifying features and achieving classification. Experiments were conducted by using a publicly available infrared image dim-small drone target detection dataset; the results show that the proposed method achieves an AP of 95.43% and a recall of 80.6%, which is a significant improvement over the current mainstream target detection algorithms.

Relationship between light absorption properties of black carbon and aerosol origin at a background coastal site.

As a potent climate forcer, black carbon (BC) optical properties can have significant impacts on the regional meteorology and climate. To unveil the seasonal differences of BC and its contribution by various emission sources, a one-year continuous monitoring of atmospheric aerosols was conducted at a background coastal site in Eastern China. By comparing the seasonal and diurnal patterns between BC and elemental carbon, we observed that BC were evidently aged with varying extents among all four seasons. The light absorption enhancement of BC (Eabs) was calculated as 1.89 ± 0.46, 2.40 ± 0.69, 1.91 ± 0.60, and 1.34 ± 0.28, from spring to winter, respectively, indicating that BC was more aged in summer. Contrary to the negligible impact of pollution levels on Eabs, the patterns of air masses arriving to the sampling site had a significant impact on the seasonal optical characteristics of BC. Sea breezes evidently exhibited higher Eabs than land-sourced breezes, and BC was more aged and light-absorbing with an increased contribution of marine airflows. By applying a receptor model, we resolved six emission sources as ship emission, traffic emission, secondary pollution, coal combustion, sea salt, and mineral dust. The mass absorption efficiency of BC for each source was estimated, showing the highest from the ship emission sector. This explained the highest Eabs observed in summer and sea breezes. Our study highlights that curbing emission from shipping activities is beneficial for reducing the warming effect of BC in coastal areas, particularly in the context of future rapid development of international shipping.

Storability and Linear Regression Models of Pericarp Browning and Decay in Fifty Litchi (Litchi chinensis Sonn.) Cultivars at Room Temperature Storage.

The primary cause for the limited shelf life of litchi fruit is rapid pericarp browning and decay. This study aims to evaluate the storability of 50 litchi varieties and establish a linear regression model for pericarp browning and decay based on 11 postharvest physical and chemical indices after 9 days of storage at room temperature. The results indicated that the average value of the browning index and decay rate significantly increased to 3.29% and 63.84% of 50 litchi varieties at day 9, respectively. Different litchi varieties showed different variations in appearance indicators, quality indicators, and physiological indicators. Furthermore, principal component analysis and cluster analysis revealed that Liu Li 2 Hao exhibited the highest resistance to storage, whereas Dong Long Mi Li, Jiao Pan Li, E Dan Li 2 Hao, and Ren Shan Li were not resistant. Stepwise multiple regression analysis further demonstrated that the factors were highly correlated with the decay index, with a partial correlation coefficient of 0.437 between the effective index and the decay index. Therefore, pericarp thickness, relative conductivity, pericarp laccase activity, and total soluble solids were significant indicators for the comprehensive evaluation of litchi browning and decay, and relative conductivity was the significant determinant causing fruit browning. These findings provide a new perspective on the sustainable development of the litchi industry.

Celastrol directly binds with VAMP7 and RAB7 to inhibit autophagy and induce apoptosis in preadipocytes.

Obesity is one of the most prevalent chronic metabolic diseases, and induction of apoptosis in preadipocytes and adipocytes is a potential strategy to treat obesity. Celastrol represents one of the most robust anti-obesity phytochemicals so far, yet its direct binding target remains elusive. Here, we determined that celastrol could induce apoptosis in preadipocytes via mitochondrial mediated pathway. Further study clarified that celastrol inhibited the fusion of autophagosome and lysosome to prohibit autophagy, leading to cell apoptosis. By conducting virtual screening and genetic manipulation, we verified that overexpression of VAMP7 and RAB7 could block the effects of celastrol on inhibiting autophagy and inducing apoptosis. The Surface Plasmon Resonance study confirmed the direct binding of celastrol with VAMP7 and RAB7. The functional study illustrated the inhibition of RAB7 GTPase activity after celastrol treatment. Moreover, celastrol induced comparable apoptosis in murine epididymal adipose tissue, human preadipocytes and adipocytes, but not in human hepatocytes. An inhibitory effect on differentiation of human primary visceral preadipocytes was also observed. In conclusion, celastrol exhibited inhibitory effect of autophagy via direct binding with VAMP7 and RAB7, leading to an increase in preadipocytes apoptosis. These results advance our understanding in the potential application of celastrol in treating obesity.

Multimodal Emotion Recognition Based on Cascaded Multichannel and Hierarchical Fusion.

Humans express their emotions in a variety of ways, which inspires research on multimodal fusion-based emotion recognition that utilizes different modalities to achieve information complementation. However, extracting deep emotional features from different modalities and fusing them remain a challenging task. It is essential to exploit the advantages of different extraction and fusion approaches to capture the emotional information contained within and across modalities. In this paper, we present a novel multimodal emotion recognition framework called multimodal emotion recognition based on cascaded multichannel and hierarchical fusion (CMC-HF), where visual, speech, and text signals are simultaneously utilized as multimodal inputs. First, three cascaded channels based on deep learning technology perform feature extraction for the three modalities separately to enhance deeper information extraction ability within each modality and improve recognition performance. Second, an improved hierarchical fusion module is introduced to promote intermodality interactions of three modalities and further improve recognition and classification accuracy. Finally, to validate the effectiveness of the designed CMC-HF model, some experiments are conducted to evaluate two benchmark datasets, IEMOCAP and CMU-MOSI. The results show that we achieved an almost 2%∼3.2% increase in accuracy of the four classes for the IEMOCAP dataset as well as an improvement of 0.9%∼2.5% in the average class accuracy for the CMU-MOSI dataset when compared to the existing state-of-the-art methods. The ablation experimental results indicate that the cascaded feature extraction method and the hierarchical fusion method make a significant contribution to multimodal emotion recognition, suggesting that the three modalities contain deeper information interactions of both intermodality and intramodality. Hence, the proposed model has better overall performance and achieves higher recognition efficiency and better robustness.

A satellite-driven model to estimate long-term particulate sulfate levels and attributable mortality burden in China.

Ambient fine particulate matter (PM2.5) pollution is a major environmental and public health challenge in China. In the recent decade, the PM2.5 level has decreased mainly driven by reductions in particulate sulfate as a result of large-scale desulfurization efforts in coal-fired power plants and industrial facilities. Emerging evidence also points to the differential toxicity of particulate sulfate affecting human health. However, estimating the long-term spatiotemporal trend of sulfate is difficult because a ground monitoring network of PM2.5 constituents has not been established in China. Spaceborne sensors such as the Multi-angle Imaging SpectroRadiometer (MISR) instrument can provide complementary information on aerosol size and type. With the help of state-of-the-art machine learning techniques, we developed a sulfate prediction model under support from available ground measurements, MISR-retrieved aerosol microphysical properties, and atmospheric reanalysis data at a spatial resolution of 0.1°. Our sulfate model performed well with an out-of-bag cross-validationR2 of 0.68 at the daily level and 0.93 at the monthly level. We found that the national mean population-weighted sulfate concentration was relatively stable before the Air Pollution Prevention and Control Action Plan was enforced in 2013, ranging from 10.4 to 11.5 µg m-3. But the sulfate level dramatically decreased to 7.7 µg m-3 in 2018, with a change rate of -28.7 % from 2013 to 2018. Correspondingly, the annual mean total non-accidental and cardiopulmonary deaths attributed to sulfate decreased by 40.7 % and 42.3 %, respectively. The long-term, full-coverage sulfate level estimates will support future studies on evaluating air quality policies and understanding the adverse health effect of particulate sulfate.

Seasonal source identification and formation processes of marine particulate water soluble organic nitrogen over an offshore island in the East China Sea.

Water soluble organic nitrogen (WSON) had great influences on the aerosol chemistry, hygroscopicity, marine primary productivity, as well as nitrogen biogeochemical cycles. Aerosol sampling was conducted over an offshore island in the East China Sea in four seasons of 2019, aiming to reveal the seasonal sources and secondary formation processes of marine WSON. The annual mean WSON concentration reached 1.05 ± 1.72 µg/m3 with a mean WSON/WSTN fraction of 27 %. In spring, WSON was associated with combustion emissions. The liquid-phase reaction of NH3/NH4+ with VOCs was a potential secondary formation process of WSON. In summer, WSON was mainly formed through the gaseous phase oxidation of marine biogenic precursors. In autumn, WSON showed miscellaneous sources from agricultural activities, biomass burning, and fossil fuel combustion. In addition to the contribution from primary urea, WSON could be also affected by the oxidation of biological proteinaceous matters. This explained the highest WSON concentrations and WSON/WSOC ratios in autumn. In winter, WSON was probably emitted from sea spray aerosols via the bubble-bursting processes. This study indicated that the sources of WSON over the coastal waters in the East China Sea were quite diverse, highlighting the need of more detailed characterization of marine WSON at the molecular level.