Search

Macrophage is located in different tissue to serve diverse functions. Here the authors use mass spectrometry and bulk RNA-sequencing to profile 11 mouse macrophage populations from 8 tissues, and combine their de novo data with public datasets to report an integrated proteomic and transcriptomic landscape of mouse macrophage as a valuable resource.

The microscale mechanisms underlying the suction anchor–sandy soil interaction under slidable pulling actions of mooring lines remain poorly understood. This technical note addresses this knowledge gap by investigating the suction anchor–sandy soil interaction from micro to macro, with a particular emphasis on the effect of interface friction. The discrete element method (DEM) was utilized to simulate the sandy soil, while the finite element method (FEM) was employed to model the suction anchors. The peak pulling forces in numerical simulations were verified by centrifuge test results. The research findings highlight the significant influence of interface friction on the pulling force–displacement curves, as it affects the patterns of suction anchor–sandy soil interactions. Furthermore, clear relationships were established between the magnitude of interface friction, rotation angle, and pullout displacement of suction anchors. By examining the macro-to-micro behaviors of suction anchor–sandy soil interactions, this study concludes with a comprehensive understanding of failure patterns and their key characteristics under different interface friction conditions. The findings proved that the interface friction not only influences the anti-pullout capacity but also changes the failure patterns of suction anchor–soil interactions in marine engineering.

Background: ACSMs play critical roles in lipid metabolism; however, their immunological function within the tumor microenvironment (TME) remains unclear, especially that of ACSM6. In this study, we investigate the latent effect of ACSM6 on bladder cancer (BLCA).Methods: Several real-world cohorts, including the Xiangya (in-house), The Cancer Genome Atlas (TCGA-BLCA), and IMvigor210 cohorts, with TCGA-BLCA cohort serving as the discovery cohort were compared. We investigated the potential immunological effects of ACSM6 in regulating the BLCA tumor microenvironment by analyzing its correlation with immunomodulators, anti-cancer immune cycles, immune checkpoints, tumor-infiltrating immune cells, and the T-cell inflamed score (TIS). Additionally, we assessed the precision of ACSM6 in predicting BLCA molecular subtypes and responses to several treatments using ROC analysis. To ensure the robustness of our findings, all results were confirmed in two independent external cohorts: the IMvigor210 and Xiangya cohorts.Results: ACSM6 expression was markedly upregulated in BLCA. Our analysis suggests that ACSM6 might have significant impact to promote the formation of a non-inflamed tumor microenvironment because of its negative correlation with immunomodulators, anticancer immune cycles, immune checkpoints, tumor-infiltrating immune cells, and the T-cell inflamed score (TIS). Additionally, high ACSM6 expression levels in BLCA may predict the luminal subtype, which is typically associated with resistance to chemotherapy, neoadjuvant chemotherapy, and radiotherapy. These findings were consistent across both the IMvigor210 and Xiangya cohorts.Conclusion: ACSM6 has the potential to serve as a valuable predictor of the tumor microenvironment phenotypes and treatment outcomes in BLCA, thereby contributing to more precise treatment.

Abstract Background Neuroinflammation in spinal dorsal horn (SDH) plays an important role in the pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS). Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) exert potent anti-inflammatory activities in the treatment of various diseases. This study aimed to determine the therapeutic effects of MSC-EVs on IC and furtherly investigate the potential mechanism to attenuate neuroinflammation. Methods Female IC rat model was established by intraperitoneal injection of cyclophosphamide (50 mg/kg, every 3 days for 3 doses). Inhibition of NLRP3 inflammasome was performed by intraperitoneal injection of MCC950 (10 mg/kg). MSC-EVs were isolated from the culture supernatants of human umbilical cord derived MSCs using ultracentrifugation, and then injected intrathecally into IC rats (20 μg in 10 μl PBS, every other day for 3 doses). Suprapubic mechanical allodynia was assessed using up-down method with von Frey filaments, and micturition frequency was examined by urodynamics. The expression of NLRP3 inflammasome components (NLRP3 and Caspase-1), glial cell markers (IBA-1 and GFAP), proinflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-18) and TLR4/NF-κB signal pathway (TLR4, p65 NK-κB and phospho-p65 NK-κB) in L6–S1 SDH was measured by Western blot analysis. The cellular localization of NLRP3 in SDH was detected using immunofluorescence co-staining. Results NLRP3 inflammasome was activated in neurons in SDH of IC rats. NLRP3 inflammasome activation contributed to activation of glial cells and process of spinal neuroinflammation in IC rats, and was related to suprapubic mechanical allodynia and frequent micturition. Intrathecal injection of MSC-EVs alleviated suprapubic mechanical allodynia and frequent micturition in IC rats, restrained activation of glial cells and attenuated neuroinflammation in SDH. In addition, MSC-EV treatment significantly inhibited activation of both NLRP3 inflammasomes and TLR4/NF-κB signal pathway. Conclusions NLRP3 inflammasome activation is involved in the neuroinflammation of IC. Intrathecal injection of MSC-EVs alleviates neuroinflammation and mechanical allodynia in IC by inhibiting the activation of NLRP3 inflammasome, and TLR4/NF-κB signal pathway may be the potential regulatory target.

Interstitial cystitis/bladder pain syndrome (IC/BPS) seriously reduces the patient’s quality of life, yet current therapies only provide partial relief. In the spinal dorsal horn (SDH), neuroinflammation plays a pivotal role in the development of IC. Injection of human umbilical cord mesenchymal stem cells (hUMSCs) to reduce inflammation is an effective strategy, and heme oxygenase-1 (HO-1) exhibits anti-nociceptive effect in neuroinflammatory pain. This study aimed to test the therapeutic effects of hUMSCs overexpressing HO-1 on cyclophosphamide-induced cystitis rat model. Cystitis rats were transplanted with altered cells and then assessed for 3 weeks. A series of behavioral measurements would be trial including suprapubic mechanical allodynia, depressive-like behaviors, micturition frequency, and short-term memory function. Additionally, western blot, immunofluorescence staining, and ELISA kit test for anti-inflammation effect. HUMSCs were capable of being transduced to overexpress HO-1. Injection of hUMSCs overexpressing HO-1 was more effective than hUMSCs alone in alleviating behavioral symptoms in rats. Furthermore, hUMSCs overexpressing HO-1 inhibited the activation of glial and TLR4/p65/NLRP3 pathway, decreased the levels of pro-inflammatory cytokines in the SDH region. Surprisingly, it markedly increased anti-inflammatory cytokine IL-10, reduced MDA content, and protected GSH concentrations in local environment. Our results suggest that injecting hUMSCs overexpressing HO-1 intrathecally can significantly promote functional outcomes in cystitis rats by reducing neuroinflammation, at least, partly through downregulating TLR4/p65/NLRP3 signaling pathway in the SDH region. This cell therapy affords a new strategy for IC/BPS treatment.

Abstract Background In recent years, long non-coding RNAs (lncRNAs) have attracted much attention because of its regulatory role in occurrence and progression of tumors, including triple-negative breast cancer (TNBC). LncRNA PITPNA antisense RNA 1 (PITPNA-AS1) has been explored in some cancers, whereas its function and molecular mechanism in TNBC remain unclear. Methods PITPNA-AS1 expression in TNBC tissues and cells was determined by RT-qPCR. TNBC cell viability, proliferation, migration, invasion were assessed with CCK-8, colony formation, wound healing, transwell assays. Cell apoptosis was evaluated by flow cytometry. Expression of EMT-related markers was detected by western blot analyses. The molecular mechanism of PITPNA-AS1 was explored by RNA pull down, luciferase reporter, RIP and ChIP assays. Results PITPNA-AS1 showed high expression levels in TNBC tissues and cells. PITPNA-AS1 knockdown suppressed TNBC cell viability, proliferation, migration, invasion in vitro and inhibited xenograft tumor growth in mice. Mechanistically, PITPNA-AS1 upregulated SIK2 expression by sponging miR-520d-5p and recruiting DDX54 protein. Results of rescue assays suggested that the inhibitive effects of silenced PITPNA-AS1 on TNBC cellular processes were partially rescued by overexpressing SIK2 or combination of miR-520d-5p inhibition and DDX54 overexpression. More importantly, we found that the upregulation of PITPNA-AS1 in TNBC cells was attributed to transcription factor MYBL2. Conclusion PITPNA-AS1 activated by MYBL2 plays an oncogenic role in TNBC through upregulating SIK2.

Abstract Background With widespread clinical application of imaging techniques, renal space-occupying lesions have been identified at an increasing frequency. Here, we report two rare cases, Castleman disease (CD) and IgG4-related disease (IgG4-RD), presenting primarily with the symptoms and imaging findings of kidney malignancy. Case presentation In case 1, an occupying lesion located in the right renal pelvis was detected using magnetic resonance imaging in a 32-year-old female who presented with hematuria and lumbago. First misdiagnosed as carcinoma of the renal pelvis, the patient underwent right radical nephroureterectomy. However, postoperative pathological and immunohistochemistry studies finally confirmed the diagnosis of CD. In case 2, a 45-year-old male presented with the chief complaint of anuria. Nephrostomy and renal biopsy indicated lymphoma, following which, antegrade urography and computed tomography urography were performed, which revealed bilateral hydronephrosis and mass lesions around the renal pelvis. Partial resection of the masses and frozen section examination indicated the diagnosis of CD. However, the results of postoperative histopathology and immunohistochemistry combined with serum IgG4 were consistent with IgG4-RD. Both the patients recovered well after drug treatment without recurrence of the diseases. Conclusions Inflammatory pseudotumor of CD and IgG4-RD with kidney involvement are primarily diagnosed by postoperative histopathology and can pose a preoperative diagnostic challenge because these lesions can masquerade as kidney malignancy. Therefore, we recommend core biopsy as a nonnegligible procedure to evaluate renal masses and potentially prevent unnecessary surgical treatment.

The reliability of disc cutters has a significant influence on the safety and working efficiency of tunnel boring machines (TBMs). To investigate the reliability of disc cutters under different geological and operational conditions, we conducted a series of novel rolling cutting tests on intact and jointed sandstone blocks using different dip angles and interlayers. Different normal forces and rotational speeds of the cutterhead were also applied during the experiment. A novel reliability estimation method, based on a logistic regression model, was then proposed, and the influence of dip angle, strata, normal force, and rotational speed on the reliability of the disc cutter were analyzed. The reliability estimation method consisted of data acquisition regarding the normal force and cutter wear, feature extraction using wavelet packet transform and correlation analysis, and the estimation of the logistic regression model. To obtain the spectrum and normalized wavelet energy for each frequency band, we decomposed the time domain of the normal force by the wavelet packet transform. A correlation analysis was employed to determine the feature frequency bands that were sensitive to wear loss. On the basis of salient feature parameters and wear loss, the logistic regression model was established to evaluate the reliability of disc cutters. The analytical results indicated that the optimal dip angle for rock cutting was 30°. In the presence of mixed-face and single ground, the reliability of disc cutters was primarily affected by the difficulty of TBM excavation and wear loss, respectively. An increase in normal force and rotational speed aggravated wear on the cutter, thus reducing reliability. Furthermore, compared with Rabinowicz’s formula, the proposed method considers various geological and operational conditions, making the proposed method more applicable to estimate the reliability of disc cutters.

Abstract Background Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we determined that neuroinflammation of the spinal dorsal horn (SDH) was associated with mechanisms of interstitial cystitis. Moreover, it has been shown that brain-derived neurotrophic factor (BDNF) participates in the regulation of neuroinflammation and pathological pain through BDNF-TrkB signaling; however, whether it plays a role in cyclophosphamide (CYP)-induced cystitis remains unclear. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs. Methods Systemic intraperitoneal injection of CYP was performed to establish a rat cystitis model. BDNF-TrkB signaling was modulated by intraperitoneal injection of the TrkB receptor antagonist, ANA-12, or intrathecal injection of exogenous BDNF. Mechanical allodynia in the suprapubic region was assessed using the von Frey filaments test. The expression of BDNF, TrkB, p-TrkB, Iba1, GFAP, p-p38, p-JNK, IL-1β, and TNF-α in the L6-S1 SDH was measured by Western blotting and immunofluorescence analysis. Results BDNF-TrkB signaling was upregulated significantly in the SDH after CYP was injected. Similarly, the expressions of Iba1, GFAP, p-p38, p-JNK, IL-1β, and TNF-α in the SDH were all upregulated. Treatment with ANA-12 could attenuate mechanical allodynia, restrain activation of astrocytes and microglia and alleviate neuroinflammation. Besides, the intrathecal injection of exogenous BDNF further decreased the mechanical withdrawal threshold, promoted activation of astrocytes and microglia, and increased the release of TNF-α and IL-1β in the SDH of our CYP-induced cystitis model. Conclusions In our CYP-induced cystitis model, BDNF promoted the activation of astrocytes and microglia to release TNF-α and IL-1β, aggravating neuroinflammation and leading to mechanical allodynia through BDNF-TrkB-p38/JNK signaling.

NLRP3 inflammasome is involved in the pathology of multiple human inflammatory diseases but there are still no clinically available medications targeting the NLRP3 inflammasome. We have previously identified RRx-001 as a highly selective and potent NLRP3 inhibitor, however, it contains high-energy nitro functional groups and may cause potential processing problems and generates highly toxic oxidants. Here, we show that compound 149-01, an RRx-001 analogue without high-energy nitro functional groups, is a potent, specific and covalent NLRP3 inhibitor. Mechanistically, 149-01 binds directly to cysteine 409 of NLRP3 to block the NEK7-NLRP3 interaction, thereby preventing NLRP3 inflammasome complex assembly and activation. Furthermore, treatment with 149-01 effectively alleviate the severity of several inflammatory diseases in mice, including lipopolysaccharide (LPS)-induced systemic inflammation, monosodium urate crystals (MSU)-induced peritonitis and experimental autoimmune encephalomyelitis (EAE). Thus, our results indicate that 149-01 is a potential lead for developing therapeutic agent for NLRP3-related inflammatory diseases.

Abstract The physical and mechanical properties of rocks at high temperatures change considerably with geothermal exploitation, underground coal gasification, and nuclear engineering construction, posing a threat to the safety of underground engineering. To investigate the effect of temperature on micro‐ and macroscale damage of sandstone, a series of uniaxial compressive strength (UCS) tests were conducted using an MTS 815 mechanical testing system. Acoustic emission (AE) monitoring, scanning electron microscopy (SEM), and nuclear magnetic resonance (NMR) were also employed. Macroscopically, it was found that the physical and mechanical properties of sandstone change with treatment temperature, but these changes do not follow a monotonic trend. In addition, the brittle‐ductile transition occurs at approximately 600°C, which is further confirmed by AE monitoring. Regarding the microstructural evolution of sandstone, the percentage of micropores shows a monotonically decreasing trend with increasing treatment temperature. The change in mesopores decreases slightly first, then shows a gradual increase, and finally decreases. The macropores first decrease and subsequently increase with increasing temperature. The decreasing trend of the meso‐ and macropores is attributed to thermal expansion at a relatively low temperature. However, the decrease in mesopores is due to their coalescence into macropores at higher temperatures. Furthermore, the integral value of the NMR spectrum first decreases and then increases with increasing treatment temperature, corresponding to the decrease in porosity from 25°C to 200°C, and then increases with temperature to 900°C. Finally, a constitutive model for the deformation and fracture of sandstone is established based on the effective medium theory and AE energy. The present study is helpful for improving the understanding of the process of thermal damage sandstone from both micro‐ and macroscale perspectives.

Argillization is a process in which clay-bearing rocks disintegrate into the clay under the action of high temperature, pressure, and water. When tunnel boring machines (TBMs) excavate in the mudstone, argillization takes place, causing the clogging of the TBM cutterhead. As a result, the penetration rate drops gradually. Abnormal wear might occur. To investigate the evolution of argillization of mudstone and cutter wear during the TBM tunnelling, a series of rotary indentation tests were carried out on the self-designed experimental bench for different loading times. During the test, the temperature and penetration depth of disc cutters were measured in real time. After loading, microstructures of cutting grooves, slacking mudstone, and worn cutter ring were observed by stereomicroscope. Consequently, the evolution of argillization in mudstone and cutter wear were investigated. Experimental results indicate that the argillization process of mudstone by disc cutter can be divided into three stages: mechanical cutting stage, deterioration of mudstone and the formation of slacking mudstone stage, and adherence of slacking mudstone stage. Specifically, at mechanical cutting stage, the rock was cut by cutter directly, causing high frictional heat. Then the microstructure of mudstone was deteriorated due to the water-weakening mechanisms, temperature effect, and mechanical activation effect. Finally, the slacking mudstone was adhered to the disc cutter. Correspondingly, due to the argillization of mudstone, the disc cutter wear goes through the mechanical wear stage, argillization wear stage, and secondary wear stage in sequence. This investigation reveals the rock cutting mechanism of TBM considering the argillization of mudstone. Furthermore, it provides some references for design and operation of the TBM.

Aims. Notch1 signaling regulates microglia activation, which promotes neuroinflammation. Neuroinflammation plays an essential role in various kinds of pain sensation, including bladder-related pain in bladder pain syndrome/interstitial cystitis (BPS/IC). However, the impact of Notch1 signaling on mechanical allodynia in cyclophosphamide- (CYP-) induced cystitis is unclear. This study is aimed at determining whether and how Notch1 signaling modulates mechanical allodynia of CYP-induced cystitis. Methods. CYP was peritoneally injected to establish a bladder pain syndrome/interstitial cystitis (BPS/IC) rat model. A γ-secretase inhibitor, DAPT, was intrathecally injected to modulate Notch1 signaling indirectly. Mechanical withdrawal threshold in the lower abdomen was measured with von Frey filaments using the up-down method. The expression of Notch1 signaling, Iba-1, OX-42, TNF-α, and IL-1β in the L6-S1 spinal dorsal horn (SDH) was measured with Western blotting analysis and immunofluorescence staining. Results. Notch1 and Notch intracellular domain (NICD) were both upregulated in the SDH of the cystitis group. Moreover, the expression of Notch1 and NICD was negatively correlated with the mechanical withdrawal threshold of the cystitis rats. Furthermore, treatment with DAPT attenuated mechanical allodynia in CYP-induced cystitis and inhibited microglia activation, leading to decreased production of TNF-α and IL-1β. Conclusion. Notch1 signaling contributes to mechanical allodynia associated with CYP-induced cystitis by promoting microglia activation and neuroinflammation. Our study showed that inhibition of Notch1 signaling might have therapeutic value for treating pain symptoms in BPS/IC.

In order to reduce the additional resistance of high-speed amphibious vehicles, Flanks are designed on the concave grooves. As a new drag reduction attachment, the principle of Flanks is analyzed and discussed in detail. In this paper, the HSAV model and Flanks coupling resistance tests are performed based on the Reynolds-averaged Navier–Stokes method and SST k−ω model. The accuracy of the numerical approach is verified by a series of towing tests. Results show that with a fixed installation angle and invariable characteristic parameters, Flanks can significantly reduce the total resistance at high speed, with a maximum drag reduction of 16%. In the meantime, Flanks also affect the attitude and flow field of the vehicle, consequently affecting the resistance composition and the sailing condition. A vehicle model self-propulsion test is designed and carried out, and it qualitatively verifies the drag reduction effect of the Flanks at high speed.

Jointed rock masses are frequently encountered during the TBM excavation. To investigate the rock breakage mechanism of jointed rock mass by disc cutter and precursory information before rock failure, a series of indentation tests were performed on shear rheological test system. During the test, breaking process of specimens were recorded by digital image correlation system and thermal infrared imager simultaneously. Therefore, the strain fields and thermal infrared images of jointed rock mass by disc cutters were obtain. The experimental results show that the failure process of jointed rock mass can be divided into four stages: compaction stage, linear elastic stage, residual failure transition stage and post-failure stage. Besides, the characteristic of strain fields shows a good accordance with that of infrared radiation temperature fields at each stage. The failure of rock samples is dominated by shear failure, and the localized temperature rise is an important infrared precursor of rock fracture and instability. The experimental results are of great significance to the deep understanding of the breaking mechanism of jointed rock mass and warnings of engineering disasters.