[Effects of Long-term Fertilizations on the Organic Carbon Components of Soil Macroaggregates and the Yield of Wheat in Wheat Fields on the Loess Plateau].

Soil macro-aggregates are the main location for soil organic carbon （SOC） sequestration, which is of great significance to improve soil fertility. This study aimed to understand the mechanisms of the organic carbon （OC） sequestration in macroaggregates and improve crop yield in wheat fields on the loess plateau. With the aggregate-density fractionation method, an eight-year experiment was conducted to investigate the following three factors： ① the effects of long-term fertilization on OC fractions within macroaggregates； ② the variation characteristics of OC fractions within macroaggregates, including coarse particulate organic carbon （cPOC）, fine particulate organic carbon （fPOC）, intra-microaggregate particulate organic carbon （iPOC）, free silt and clay particulate carbon （s+c_f）, and intra-microaggregate silt and clay particulate carbon （s+c_m）； ③ and the relationships between them and SOC input and yield formation. The treatments included no fertilization （CK）, farmer pattern （NP）, optimized fertilizers pattern （NPK）, optimized fertilizers + organic fertilizers pattern （NPKM）, and optimized fertilizers + biological organic fertilizers pattern （NPKB）. The results showed that the application of organic and chemical fertilizer （NPKM and NPKB） improved significantly the SOC content in macroaggregates compared with that in the single fertilizer treatment （NP and NPK）, which had a greater increase in SOC content in macroaggregates than that of the soil. All fertilization treatments had a tendency to increase the content of fractions iPOC, fPOC, and iPOC in macroaggregates, but silt and clay carbon （s+c_f and s+c_m） contents were decreased. The application of manure combined with chemicals markedly increased the allocations of fractions cPOC, fPOC, and iPOC reserves, but it greatly decreased （s+c_f） reserves allocation. However, the application of chemical fertilizers only significantly increased the proportion of cPOC reserves in macroaggregates. Correlation analysis showed that there were significant positive correlations among wheat grain yield and OC fractions （cPOC and fPOC） contents, SOC content, the OC content of >0.25 mm macroaggregates, and SOC input, and the correlation coefficient was 0.645-0.883. In conclusion, long-term fertilization, especially combined with organic fertilizer, could promote the free silt and clay carbon fraction （s+c_f） to transfer into other forms of OC components through the increase in soil carbon input in the wheat field of the loess plateau. Furthermore, the OC content of macroaggregates was increased overall, providing a good soil environment for crop yield.

Calmodulin triggers activity-dependent rRNA biogenesis via interaction with DDX21.

Protein synthesis in response to neuronal activity, known as activity-dependent translation, is critical for synaptic plasticity and memory formation. However, the signaling cascades that couple neuronal activity to the translational events remains elusive. In this study, we identified the role of calmodulin (CaM), a conserved Ca2+-binding protein, in rRNA biogenesis in neurons. We found the CaM-regulated rRNA synthesis is Ca2+-dependent and necessary for nascent protein synthesis and axon growth in hippocampal neurons. Mechanistically, CaM interacts with nucleolar DDX21 in a Ca2+-dependent manner to regulate nascent rRNA transcription within nucleoli. We further found CaM alters the conformation of DDX21 to liberate the DDX21-sequestered RPA194, the catalytic subunit of RNA polymerase I, to facilitate transcription of rDNA. Using high-throughput screening, we identified the small molecules Batefenterol and Indacaterol that attenuate the CaM-DDX21 interaction and suppress nascent rRNA synthesis and axon growth in hippocampal neurons. These results unveiled the previously unrecognized role of CaM as a messenger to link the activity-induced Ca2+ influx to the nucleolar events essential for protein synthesis. We thus identified the ability of CaM to transmit information to the nucleoli of neurons in response to stimulation.Significance statement Protein synthesis in response to neuronal activity, known as activity-dependent translation, is critical for synaptic plasticity and long-term memory formation. In this study, we identify the novel role of calmodulin (CaM), a highly conserved Ca2+-binding protein, which is well-known by regulating myriad vital biological processes, in activity-dependent translation by regulating rRNA synthesis in neurons. We find that CaM can shuttle into the nucleolus upon depolarization and modulate the activity-induced de novo rRNA biogenesis, which is associated with ribosome assembly and protein synthesis in neurons. Mechanistically, CaM interacts with DDX21, an RNA helicase directly associated with Pol I subunit, to regulate the transcription of rDNA. Our study demonstrates CaM as a messenger linking neuronal activity to ribosome-dependent protein biosynthesis.

The roles of bacteria and viruses in COPD-Bronchiectasis association: A prospective cohort study.

BACKGROUND: Exacerbations are implicated in bronchiectasis and COPD, which frequently co-exist [COPD-Bronchiectasis association (CBA)]. We aimed to determine the bacterial and viral spectrum at stable-state and exacerbation onset of CBA, and their association with exacerbations and clinical outcomes of CBA as compared with bronchiectasis. METHODS: We prospectively collected spontaneous sputum from adults with CBA, bronchiectasis with (BO) and without airflow obstruction (BNO) for bacterial culture and viral detection at stable-state and exacerbations. RESULTS: We enrolled 76 patients with CBA, 58 with BO, and 138 with BNO (711 stable and 207 exacerbation visits). Bacterial detection rate increased from BNO, CBA to BO at steady-state (P = 0.02), but not at AE onset (P = 0.91). No significant differences in viral detection rate were found among BNO, CBA and BO. Compared with steady-state, viral isolations occurred more frequently at exacerbation in BNO (15.8 % vs 32.1 %, P = 0.001) and CBA (19.5 % vs 30.6 %, P = 0.036) only. In CBA, isolation of viruses, human metapneumovirus and bacteria plus viruses was associated with exacerbation. Repeated detection of Pseudomonas aeruginosa (PA) correlated with higher modified Reiff score (P = 0.032) in CBA but not in BO (P = 0.178). Repeated detection of PA yielded a shorter time to the first exacerbation in CBA [median: 4.3 vs 11.1 months, P = 0.006] but not in BO (median: 8.4 vs 7.6 months, P = 0.47). CONCLUSIONS: Isolation of any viruses, human metapneumovirus and bacterialplus viruses was associated with CBA exacerbations. Repeated detection of PA confers greater impact of future exacerbations on CBA than on BO.

The sphingosine-1-phosphate receptor 1 mediates the atheroprotective effect of eicosapentaenoic acid.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been associated with potential cardiovascular benefits, partly attributed to their bioactive metabolites. However, the underlying mechanisms responsible for these advantages are not fully understood. We previously reported that metabolites of the cytochrome P450 pathway derived from eicosapentaenoic acid (EPA) mediated the atheroprotective effect of ω-3 PUFAs. Here, we show that 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and its receptor, sphingosine-1-phosphate receptor 1 (S1PR1), in endothelial cells (ECs) can inhibit oscillatory shear stress- or tumor necrosis factor-α-induced endothelial activation in cultured human ECs. Notably, the atheroprotective effect of 17,18-EEQ and purified EPA is circumvented in male mice with endothelial S1PR1 deficiency. Mechanistically, the anti-inflammatory effect of 17,18-EEQ relies on calcium release-mediated endothelial nitric oxide synthase (eNOS) activation, which is abolished upon inhibition of S1PR1 or Gq signaling. Furthermore, 17,18-EEQ allosterically regulates the conformation of S1PR1 through a polar interaction with Lys34Nter. Finally, we show that Vascepa, a prescription drug containing highly purified and stable EPA ethyl ester, exerts its cardiovascular protective effect through the 17,18-EEQ-S1PR1 pathway in male and female mice. Collectively, our findings indicate that the anti-inflammatory effect of 17,18-EEQ involves the activation of the S1PR1-Gq-Ca2+-eNOS axis in ECs, offering a potential therapeutic target against atherosclerosis.

Scalable Compliant Graphene Fiber-Based Thermal Interface Material with Metal-Level Thermal Conductivity via Dual-Field Synergistic Alignment Engineering.

High-performance thermal interface materials (TIMs) are highly desired for high-power electronic devices to accelerate heat dissipation. However, the inherent trade-off conflict between achieving high thermal conductivity and excellent compliance of filler-enhanced TIMs results in the unsatisfactory interfacial heat transfer efficiency of existing TIM solutions. Here, we report the graphene fiber (GF)-based elastic TIM with metal-level thermal conductivity via mechanical-electric dual-field synergistic alignment engineering. Compared with state-of-the-art carbon fiber (CF), GF features both superb high thermal conductivity of ∼1200 W m-1 K-1 and outstanding flexibility. Under dual-field synergistic alignment regulation, GFs are vertically aligned with excellent orientation (0.88) and high array density (33.5 mg cm-2), forming continuous thermally conductive pathways. Even at a low filler content of ∼17 wt %, GF-based TIM demonstrates extraordinarily high through-plane thermal conductivity of up to 82.4 W m-1 K-1, exceeding most CF-based TIMs and even comparable to commonly used soft indium foil. Benefiting from the low stiffness of GF, GF-based TIM shows a lower compressive modulus down to 0.57 MPa, an excellent resilience rate of 95% after compressive cycles, and diminished contact thermal resistance as low as 7.4 K mm2 W-1. Our results provide a superb paradigm for the directed assembly of thermally conductive and flexible GFs to achieve scalable and high-performance TIMs, overcoming the long-standing bottleneck of mechanical-thermal mismatch in TIM design.

Advances in Nanomaterials for Immunotherapeutic Improvement of Cancer Chemotherapy.

Immuno-stimulative effect of chemotherapy (ISECT) is recognized as a potential alternative to conventional immunotherapies, however, the clinical application is constrained by its inefficiency. Metronomic chemotherapy, though designed to overcome these limitations, offers inconsistent results, with effectiveness varying based on cancer types, stages, and patient-specific factors. In parallel, a wealth of preclinical nanomaterials holds considerable promise for ISECT improvement by modulating the cancer-immunity cycle. In the area of biomedical nanomaterials, current literature reviews mainly concentrate on a specific category of nanomaterials and nanotechnological perspectives, while two essential issues are still lacking, i.e., a comprehensive analysis addressing the causes for ISECT inefficiency and a thorough summary elaborating the nanomaterials for ISECT improvement. This review thus aims to fill these gaps and catalyze further development in this field. For the first time, this review comprehensively discusses the causes of ISECT inefficiency. It then meticulously categorizes six types of nanomaterials for improving ISECT. Subsequently, practical strategies are further proposed for addressing inefficient ISECT, along with a detailed discussion on exemplary nanomedicines. Finally, this review provides insights into the challenges and perspectives for improving chemo-immunotherapy by innovations in nanomaterials.

Investigating cartilage-related diseases by polarization-resolved second harmonic generation (P-SHG) imaging.

Establishing quantitative parameters for differentiating between healthy and diseased cartilage tissues by examining collagen fibril degradation patterns facilitates the understanding of tissue characteristics during disease progression. These findings could also complement existing clinical methods used to diagnose cartilage-related diseases. In this study, cartilage samples from normal, osteoarthritis (OA), and rheumatoid arthritis (RA) tissues were prepared and analyzed using polarization-resolved second harmonic generation (P-SHG) imaging and quantitative image texture analysis. The enhanced molecular contrast obtained from this approach is expected to aid in distinguishing between healthy and diseased cartilage tissues. P-SHG image analysis revealed distinct parameters in the cartilage samples, reflecting variations in collagen fibril arrangement and organization across different pathological states. Normal tissues exhibited distinct χ33/χ31 values compared with those of OA and RA, indicating collagen type transition and cartilage erosion with chondrocyte swelling, respectively. Compared with those of normal tissues, OA samples demonstrated a higher degree of linear polarization, suggesting increased tissue birefringence due to the deposition of type-I collagen in the extracellular matrix. The distribution of the planar orientation of collagen fibrils revealed a more directional orientation in the OA samples, associated with increased type-I collagen, while the RA samples exhibited a heterogeneous molecular orientation. This study revealed that the imaging technique, the quantitative analysis of the images, and the derived parameters presented in this study could be used as a reference for disease diagnostics, providing a clear understanding of collagen fibril degradation in cartilage.

Thyroid disorders and gastrointestinal dysmotility: an old association.

Gastrointestinal motility symptoms may be closely related to thyroid diseases. Sometimes, such symptoms are the only thyroid disease-related clue although the degree of the symptoms may vary. The exact mechanism of action of thyroid hormones on gastrointestinal motility is not completely understood, however, a clue lies in the fact that muscle cell receptors can be directly acted upon by thyroxines. Both hypo- and hyperthyroidism can cause impairment of gastrointestinal motility, modifying structure and function of pharynx and esophagus, and regulating esophageal peristalsis through neuro-humoral interaction. In hyperthyroid patients, alterations of postprandial and basic electric rhythms have been observed at gastro-duodenal level, often resulting in slower gastric emptying. Gastric emptying may also be delayed in hypothyroidism, but an unrelated gastric mucosa-affecting chronic modification may also cause such pattern. Hyperthyroidism commonly show malabsorption and diarrhoea, while hypothyroidism frequently show constipation. In summary, it can be stated that symptoms of gastrointestinal motility dysfunction can be related to thyroid diseases, affecting any of the gastrointestinal segment. Clinically, the typical thyroid disease manifestations may be missing, borderline, or concealed because of intercurrent sicknesses. Motility-linked gastrointestinal problems may easily conceal a misdetected, underlying dysthyroidism that should be carefully analyzed. Here, we aim to elaborate on the associations between thyroid disorders and GI dysmotility and the common clinical manifestations associated with GI dysmotility.

Association between risk of preterm birth and long-term and short-term exposure to ambient carbon monoxide during pregnancy in chongqing, China: a study from 2016-2020.

BACKGROUND: Preterm birth (PTB) is an important predictor of perinatal morbidity and mortality. Previous researches have reported a correlation between air pollution and an increased risk of preterm birth. However, the specific relationship between short-term and long-term exposure to carbon monoxide (CO) and preterm birth remains less explored. METHODS: A population-based study was conducted among 515,498 pregnant women in Chongqing, China, to assess short-term and long-term effects of CO on preterm and very preterm births. Generalized additive models (GAM) were applied to evaluate short-term effects, and exposure-response correlation curves were plotted after adjusting for confounding factors. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using COX proportional hazard models to estimate the long-term effect. RESULTS: The daily incidence of preterm and very preterm birth was 5.99% and 0.41%, respectively. A positive association between a 100 µg/m³ increase in CO and PTB was observed at lag 0-3 days and 12-21 days, with a maximum relative risk (RR) of 1.021(95%CI: 1.001-1.043). The exposure-response curves (lag 0 day) revealed a rapid increase in PTB due to CO. Regarding long-term exposure, positive associations were found between a 100 µg/m3 CO increase for each trimester(Model 2 for trimester 1: HR = 1.054, 95%CI: 1.048-1.060; Model 2 for trimester 2: HR = 1.066, 95%CI: 1.060-1.073; Model 2 for trimester 3: HR = 1.007, 95%CI: 1.001-1.013; Model 2 for entire pregnancy: HR = 1.080, 95%CI: 1.073-1.088) and higher HRs of very preterm birth. Multiplicative interactions between air pollution and CO on the risk of preterm and very preterm birth were detected (P- interaction<0.05). CONCLUSIONS: Our findings suggest that short-term exposure to low levels of CO may have protective effects against preterm birth, while long-term exposure to low concentrations of CO may reduce the risk of both preterm and very preterm birth. Moreover, our study indicated that very preterm birth is more susceptible to the influence of long-term exposure to CO during pregnancy, with acute CO exposure exhibiting a greater impact on preterm birth. It is imperative for pregnant women to minimize exposure to ambient air pollutants.

Recovering carbon fibers from waste CFRPs via pyrolysis-oxidation method: Implications for reuse in remanufactured materials.

Carbon fiber-reinforced polymer composites (CFRPs) have gained widespread usage due to their promising physiochemical properties, while this causes large amounts of waste CFRPs worldwide. In this study, carbon fibers were successfully recovered from waste CFRPs through the pyrolysis-oxidation method, and the recovered fibers were reused in remanufacturing the secondary generation CFRPs. Moreover, the individual and interactive effects of pyrolysis-oxidation recovering parameters on the mechanical strength of the resulting remanufactured CFRPs (reCFRPs) were investigated. The recovered carbon fibers displayed surface chemical structures similar to virgin fibers but with high contents of oxygen-containing bonds. The tensile strength retention (TSR) of the reCFRPs was primarily influenced by oxidation temperature. Notably, a higher oxidation temperature, especially exceeding 560 °C, amplified the impact of oxidation duration on the TSR value. Similarly, concerning interlaminar shear strength retention (ISSR), the oxidation stage had a more substantial effect compared to the pyrolysis stage. As the oxidation temperature increased from 500 °C to 600 °C, the ISSR value initially increased and then decreased, irrespective of variations in pyrolysis parameters. Additionally, through integrating the response surface methodology (RSM) analysis and multi-island genetic algorithm (MIGA) global optimization, three recovery strategies, along with the corresponding processing parameters, were proposed to meet diverse requirements. The conclusions could provide valuable insights for optimizing the recovery and reuse of carbon fibers from waste CFRPs.

High Performance Nacre Fibers by Engineering Interfacial Entanglement.

Biological materials exhibit fascinating mechanical properties for intricate interactions at multiple interfaces to combine superb toughness with wondrous strength and stiffness. Recently, strong interlayer entanglement has emerged to replicate the powerful dissipation of natural proteins and alleviate the conflict between strength and toughness. However, designing intricate interactions in a strong entanglement network needs to be further explored. Here, we modulate interlayer entanglement by introducing multiple interactions, including hydrogen and ionic bonding, and achieve ultrahigh mechanical performance of graphene-based nacre fibers. Two essential modulating trends are directed. One is modulating dynamic hydrogen bonding to improve the strength and toughness up to 1.58 GPa and 52 MJ/m3, simultaneously. The other is tailoring ionic coordinating bonding to raise the strength and stiffness, reaching 2.3 and 253 GPa. Modulating various interactions within robust entanglement provides an effective approach to extend performance limits of bioinspired nacre and optimize multiscale interfaces in diverse composites.

The treatment of oily wastewater by thermo-responsive calcium alginate capsules immobilized Pseudomonas aeruginosa.

A microfluidic strategy of smart calcium alginate (CA) capsules is presented to immobilize Pseudomonas aeruginosa to treat oil slicks effectively. The capsule wall is embedded with poly (N-isopropyl acrylamide) sub-microspheres as thermo-responsive switches. CA capsules, with a diameter of 3.26 mm and a thin wall thickness about 12.8 µm, have satisfying monodispersity, cavity structure, and dense surface structures. The capsules possess excellent encapsulation of bacteria, which are fixed in a restricted space and become more aggregated. It overcomes the disadvantages of a long fermentation production cycle, easy loss of bacteria, and susceptibility to shear effect. The smart CA capsules immobilized with bacteria treat model wastewater containing soybean oil or diesel and display favorable fermentation ability. The capsules can effectively treat oil slicks with high concentration, and it is an economical way for processing oily wastewater. PRACTITIONER POINTS: A thermo-responsive calcium alginate capsule was prepared by microfluidic strategy. Pseudomonas aeruginosa is environmentally friendly in treating oil slicks. The capsules, immobilized bacteria, treat oil slicks effectively. This study provides an economical way for processing different oily water.

Determinative scrolling and folding of membranes through shrinking channels.

Flat membranes ubiquitously transform into mysterious complex shapes in nature and artificial worlds. Behind the complexity, clear determinative deformation modes have been continuously found to serve as basic application rules but remain unfulfilled. Here, we decipher two elemental deformation modes of thin membranes, spontaneous scrolling and folding as passing through shrinking channels. We validate that these two modes rule the deformation of membranes of a wide thickness range from micrometer to atomic scale. Their occurrence and the determinative fold number quantitatively correlate with the Föppl-von Kármán number and shrinkage ratio. The unveiled determinative deformation modes can guide fabricating foldable designer microrobots and delicate structures of two-dimensional sheets and provide another mechanical principle beyond genetic determinism in biological morphogens.

Explore the effect of apparent temperature and air pollutants on the admission rate of acute myocardial infarction in Chongqing, China: a time-series study.

OBJECTIVE: Limited research has been conducted on the correlation between apparent temperature and acute myocardial infarction (AMI), as well as the potential impact of air pollutants in modifying this relationship. The objective of this study is to investigate the lagged effect of apparent temperature on AMI and assess the effect modification of environmental pollutants on this association. DESIGN: A time-series study. SETTING AND PARTICIPANTS: The data for this study were obtained from the Academy of Medical Data Science at Chongqing Medical University, covering daily hospitalisations for AMI between 1 January 2015 and 31 December 2016. Meteorological and air pollutant data were provided by China's National Meteorological Information Centre. OUTCOME MEASURES: We used a combined approach of quasi-Poisson generalised linear model and distributed lag non-linear model to thoroughly analyse the relationships. Additionally, we employed a generalised additive model to investigate the interaction between air pollutants and apparent temperature on the effect of AMI. RESULT: A total of 872 patients admitted to hospital with AMI were studied based on the median apparent temperature (20.43°C) in Chongqing. Low apparent temperature (10th, 7.19℃) has obvious lagged effect on acute myocardial infarction, first appearing on the 8th day (risk ratio (RR) 1.081, 95% CI 1.010 to 1.158) and the greatest risk on the 11th day (RR 1.094, 95% CI 1.037 to 1.153). No lagged effect was observed at high apparent temperature. In subgroup analysis, women and individuals aged 75 and above were at high risk. The interaction analysis indicates that there exist significant interactions between PM2.5 and high apparent temperature, as well as nitrogen dioxide (NO2) and low apparent temperature. CONCLUSION: The occurrence of decreased apparent temperature levels was discovered to be linked with a heightened relative risk of hospitalisations for AMI. PM2.5 and NO2 have an effect modification on the association between apparent temperature and admission rate of AMI.

Differential contributions of G protein- or arrestin subtype-mediated signalling underlie urocortin 3-induced somatostatin secretion in pancreatic δ cells.

BACKGROUND AND PURPOSE: Pancreatic islets are modulated by cross-talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic ß cells activates the CRF2 receptor (CRF2R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis. EXPERIMENTAL APPROACH: Here, we used Arrb1-/-, Arrb2-/-, Gsfl/fl and Gqfl/fl knockout mice, the G11-shRNA-GFPfl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of Gs, G11 and ß-arrestin1 to CRF2R contributed to UCN3-induced SST secretion in pancreatic δ cells. KEY RESULTS: Our study showed that CRF2R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs-mediated UCN3- CRF2R axis for SST secretion, the interaction of SYT1 with ß-arrestin1 is also essential for efficient SST secretion downstream of CRF2R. The specific expression of the transcription factor Stat6 may contribute to G11 expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF2R downstream effectors. CONCLUSIONS AND IMPLICATIONS: Collectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3- CRF2R signalling in pancreatic ß-δ-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks.

Hyperoside induces cell cycle arrest and suppresses tumorigenesis in bladder cancer through the interaction of EGFR-Ras and Fas signaling pathways.

Hyperoside is a natural flavonol glycoside widely found in plants and has been reported to have a variety of pharmacological effects, including anticancer abilities. In this study, we demonstrated for the first time that hyperoside inhibited the proliferation of bladder cancer cells in vitro and in vivo. Moreover, hyperoside could not only induce cell cycle arrest, but also induce apoptosis of a few bladder cancer cells. Quantitative proteomics, bioinformatics analysis and Western blotting confirmed that hyperoside induced the overexpression of EGFR, Ras and Fas proteins, which affects a variety of synergistic and antagonistic downstream signaling pathways, including MAPKs and Akt, ultimately contributing to its anticancer effects in bladder cancer cells. This study reveals that hyperoside could be a promising therapeutic strategy for the prevention of bladder cancer.

Classification and hemodynamic characteristics of delayed intracerebral hemorrhage following stent-assisted coil embolism in unruptured intracranial aneurysms.

Background and objective: Stent-assisted coil (SAC) embolization is a commonly used endovascular treatment for unruptured intracranial aneurysms (UIAs) but can be associated with symptomatic delayed intracerebral hemorrhage (DICH). Our study aimed to investigate the hemodynamic risk factors contributing to DICH following SAC embolization and to establish a classification for DICH predicated on hemodynamic profiles. Methods: This retrospective study included patients with UIAs located in the internal carotid artery (ICA) treated with SAC embolization at our institution from January 2021 to January 2022. We focused on eight patients who developed postoperative DICH and matched them with sixteen control patients without DICH. Using computational fluid dynamics, we evaluated the hemodynamic changes in distal arteries [terminal ICA, the anterior cerebral artery (ACA), and middle cerebral artery (MCA)] pre-and post-embolization. We distinguished DICH-related arteries from unrelated ones (ACA or MCA) and compared their hemodynamic alterations. An imbalance index, quantifying the differential in flow velocity changes between ACA and MCA post-embolization, was employed to gauge the flow distribution in distal arteries was used to assess distal arterial flow distribution. Results: We identified two types of DICH based on postoperative flow alterations. In type 1, there was a significant lower in the mean velocity increase rate of the DICH-related artery compared to the unrelated artery (-47.25 ± 3.88% vs. 42.85 ± 3.03%; p < 0.001), whereas, in type 2, there was a notable higher (110.58 ± 9.42% vs. 17.60 ± 4.69%; p < 0.001). Both DICH types demonstrated a higher imbalance index than the control group, suggesting an association between altered distal arterial blood flow distribution and DICH occurrence. Conclusion: DICH in SAC-treated UIAs can manifest as either a lower (type 1) or higher (type 2) in the rate of velocity in DICH-related arteries. An imbalance in distal arterial blood flow distribution appears to be a significant factor in DICH development.

Monocytes Release Pro-Cathepsin D to Drive Blood-to-Brain Transcytosis in Diabetes.

BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.