Background
As obesity becomes more prevalent, it becomes more common among patients considering orthopaedic surgery, including spinal surgery. However, there is some controversy regarding whether ...obesity is associated with complications, failed reconstructions, or reoperations after spinal surgery.
Questions/purposes
We wished to determine, in patients undergoing spine surgery, whether obesity is associated with (1) surgical site infection, (2) mortality and the need for revision surgery after spinal surgery, and (3) increased surgical time and blood loss.
Methods
A systematic literature search was performed to collect comparative or controlled studies that evaluated the influence of obesity on the surgical and postoperative outcomes of spinal surgery. Two reviewers independently selected trials, extracted data, and assessed the methodologic quality and quality of evidence. Pooled odds ratios (OR) and mean differences (MD) with 95% CIs were calculated using the fixed-effects model or random-effects model. Data were analyzed using RevMan 5.1. MOOSE criteria were used to ensure this project’s validity. Thirty-two studies involving 97,326 patients eventually were included.
Results
Surgical site infection (OR, 2.33; 95% CI, 1.94–2.79), venous thromboembolism (OR, 3.15; 95% CI, 1.92–5.17), mortality (OR, 2.6; 95% CI, 1.50–4.49), revision rate (OR, 1.43; 95% CI, 1.05–1.93) operating time (OR, 14.55; 95% CI, 10.03–19.07), and blood loss (MD, 28.89; 95% CI, 14.20–43.58), were all significantly increased in the obese group.
Conclusion
Obesity seemed to be associated with higher risk of surgical site infection and venous thromboembolism, more blood loss, and longer surgical time. Future prospective studies are needed to confirm the relationship between obesity and the outcome of spinal surgery.
This paper presents unique approaches to enable control and quantification of ultrasound-mediated cell membrane disruption, or sonoporation, at the single-cell level. Ultrasound excitation of ...microbubbles that were targeted to the plasma membrane of HEK-293 cells generated spatially and temporally controlled membrane disruption with high repeatability. Using whole-cell patch clamp recording combined with fluorescence microscopy, we obtained time-resolved measurements of single-cell sonoporation and quantified the size and resealing rate of pores. We measured the intracellular diffusion coefficient of cytoplasmic RNA/DNA from sonoporation-induced transport of an intercalating fluorescent dye into and within single cells. We achieved spatiotemporally controlled delivery with subcellular precision and calcium signaling in targeted cells by selective excitation of microbubbles. Finally, we utilized sonoporation to deliver calcein, a membrane-impermeant substrate of multidrug resistance protein-1 (MRP1), into HEK-MRP1 cells, which overexpress MRP1, and monitored the calcein efflux by MRP1. This approach made it possible to measure the efflux rate in individual cells and to compare it directly to the efflux rate in parental control cells that do not express MRP1.
Altered freeze‐thaw cycle (FTC) patterns due to global climate change may affect nitrogen (N) cycling in terrestrial ecosystems. However, the general responses of soil N pools and fluxes to different ...FTC patterns are still poorly understood. Here, we compiled data of 1519 observations from 63 studies and conducted a meta‐analysis of the responses of 17 variables involved in terrestrial N pools and fluxes to FTC. Results showed that under FTC treatment, soil NH4+, NO3−, NO3− leaching, and N2O emission significantly increased by 18.5%, 18.3%, 66.9%, and 144.9%, respectively; and soil total N (TN) and microbial biomass N (MBN) significantly decreased by 26.2% and 4.7%, respectively; while net N mineralization or nitrification rates did not change. Temperate and cropland ecosystems with relatively high soil nutrient contents were more responsive to FTC than alpine and arctic tundra ecosystems with rapid microbial acclimation. Therefore, altered FTC patterns (such as increased duration of FTC, temperature of freeze, amplitude of freeze, and frequency of FTC) due to global climate warming would enhance the release of inorganic N and the losses of N via leaching and N2O emissions. Results of this meta‐analysis help better understand the responses of N cycling to FTC and the relationships between FTC patterns and N pools and N fluxes.
1. Freeze‐thaw cycle significantly increased inorganic N, NO3− leaching, and N2O emission, but significantly decreased soil total N and microbial biomass nitrogen. 2. Temperate and cropland ecosystems with relatively high soil nutrient contents were more responsive to FTC than alpine and arctic tundra ecosystems with rapid microbial acclimation. 3. Altered FTC patterns (such as increased duration of FTC, temperature of freeze, amplitude of freeze, and frequency of FTC) due to global climate warming would enhance the release of inorganic N and the losses of N via leaching and N2O emissions.
Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes remain to be systemically identified for lung cancer. Through the genome-wide screening of ...tumor-suppressive transcription factors, we demonstrate here that GATA4 functions as an essential tumor suppressor in lung cancer in vitro and in vivo. Ectopic GATA4 expression results in lung cancer cell senescence. Mechanistically, GATA4 upregulates multiple miRNAs targeting TGFB2 mRNA and causes ensuing WNT7B downregulation and eventually triggers cell senescence. Decreased GATA4 level in clinical specimens negatively correlates with WNT7B or TGF-β2 level and is significantly associated with poor prognosis. TGFBR1 inhibitors show synergy with existing therapeutics in treating GATA4-deficient lung cancers in genetically engineered mouse model as well as patient-derived xenograft (PDX) mouse models. Collectively, our work demonstrates that GATA4 functions as a tumor suppressor in lung cancer and targeting the TGF-β signaling provides a potential way for the treatment of GATA4-deficient lung cancer.
Small molecular PD‐1 inhibitors are lacking in current immuno‐oncology clinic. PD‐1/PD‐L1 antibody inhibitors currently approved for clinical usage block interaction between PD‐L1 and PD‐1 to enhance ...cytotoxicity of CD8+ cytotoxic T lymphocyte (CTL). Whether other steps along the PD‐1 signaling pathway can be targeted remains to be determined. Here, we report that methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, potently inhibits PD‐1 signaling. MB enhances the cytotoxicity, activation, cell proliferation, and cytokine‐secreting activity of CTL inhibited by PD‐1. Mechanistically, MB blocks interaction between Y248‐phosphorylated immunoreceptor tyrosine‐based switch motif (ITSM) of human PD‐1 and SHP2. MB enables activated CTL to shrink PD‐L1 expressing tumor allografts and autochthonous lung cancers in a transgenic mouse model. MB also effectively counteracts the PD‐1 signaling on human T cells isolated from peripheral blood of healthy donors. Thus, we identify an FDA‐approved chemical capable of potently inhibiting the function of PD‐1. Equally important, our work sheds light on a novel strategy to develop inhibitors targeting PD‐1 signaling axis.
Synopsis
PD‐1 inhibitors that are currently used in the clinic exhibit toxicity and limited patient response rate. This study identifies methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, as a new potent PD‐1 inhibitor.
MB activates T‐cell functions through inhibiting the recruitment of SHP2 to PD‐1.
MB treatment effectively shrinks tumors in both an allograft mouse model and an autochthonous mouse model for lung cancer.
MB activates human CD8+ T cells that are otherwise suppressed by PD‐1 signaling.
PD‐1 inhibitors that are currently used in the clinic exhibit toxicity and limited patient response rate. This study identifies methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, as a new potent PD‐1 inhibitor.
Background
Neuroinflammation, mediated by the activation of microglia, contributes to central sensitization, which is associated with the development of chronic migraine (CM). TREM1 receptors amplify ...the inflammatory response. However, their relationship to CM is unclear. Thus, this study endeavoured to elucidate the exact role of TREM1 in CM.
Methods
Nitroglycerin (NTG) was repeatedly administered intraperitoneally to establish the CM model. Mechanical and thermal sensitivities were assessed using von Frey filaments and hot plate assays. Using Western blotting, TREM1, NF-κB pathway, NLRP3 inflammasome components, and proinflammatory cytokines were all detected. Immunofluorescence was used to examine the cellular distribution of TREM1 and NLRP3, the number of microglia, immunoreactivity, and morphological changes. We examined the effects of TREM1 antagonists (LR12) and NF-κB inhibitors (PDTC) on pain behaviour, as well as the production of c-fos and CGRP. Additionally, we investigated whether LR12 and PDTC affect the activation of microglia and the NLRP3 inflammasome. We synthesized siRNA and TREM1-overexpressing plasmids to transfect BV2 cells treated with LPS and normal BV2 cells and treated TREM1-overexpressing BV2 cells with PDTC. The NF-κB pathway, NLRP3 inflammasome components, and proinflammatory cytokines were quantified using Western blotting.
Results
Following NTG administration, the expression of TREM1 was significantly upregulated and exclusively localized in microglia in the TNC, and was well co-localized with NLRP3. Furthermore, activation of the classical NF-κB pathway was observed. Pre-treatment with LR12 and PDTC effectively attenuated mechanical hypersensitivity, suppressed the expression of c-fos and CGRP, and inhibited NF-κB activity in CM mice. Additionally, inhibition of TREM1 and NF-κB activity mitigated NTG-induced microglia and NLRP3 activation, as well as proinflammatory cytokines production. In vitro, knockdown of TREM1 resulted in attenuated activation of the NF-κB pathway following lipopolysaccharide (LPS) treatment and reduced expression of NLRP3 inflammasome components as well as proinflammatory cytokines. After TREM1 overexpression, the NF-κB pathway was activated, NLRP3 inflammasome components and proinflammatory cytokines were upregulated, and PDTC reversed this phenomenon.
Conclusions
Our findings suggest that TREM1 regulates microglia and NLRP3 activation via the NF-κB pathway, thereby contributing to central sensitization and implicating its involvement in chronic migraine pathogenesis.
•Mechanochemical conversion is a key mechanism for cells to sense and respond to acoustic tweezing cytometry (ATC).•ATC parameters, especially ultrasound center frequency, significantly impact cell ...contractility responses.•It is large molecules, rather than small ions, that mediate the global responses to a local ATC stimulus.•The incorporation of visible stress fiber bundles into 2D models better recapitulates the experimental observations.•Cells on rigid substrates exhibit more traction force increases while cells on soft substrates are more sensitive to ATC.
Acoustic tweezing cytometry (ATC) is a recently developed method for cell mechanics regulation. Targeted microbubbles, which are attached to integrins and subsequently the actin cytoskeleton, anchor, amplify and transmit the mechanical energy in an acoustic field inside the cells, eliciting prominent cytoskeleton contractile force increases in various cell types. We propose that a mechanochemical conversion mechanism is critical for the high efficiency of ATC to activate cell contractility responses. Our models predict key experimental observations. Moreover, we study the influences of ATC parameters (ultrasound center frequency, pulse repetition frequency, duty cycle, and acoustic pressure), cell areas, the number of ATC stimuli, and extracellular matrix rigidity on cell contractility responses to ATC. The simulation results suggest that it is large molecules, rather than small ions, that facilitate global responses to the local ATC stimulation, and the incorporation of visible stress fiber bundles improves the accuracy of modeling.
•Chinese pine forest had higher winter soil CO2 flux than larch forest.•Snow depth and inorganic N did not explain the differences in winter CO2 flux.•Soil microbes explained the differences in ...winter CO2 flux between the two sites.•Litter layer was important to winter CO2 flux, especially when snow depth was <30 cm.
Larch and Chinese pine plantation forests are important carbon (C) sinks in the temperate regions, especially in China. However, their soil respiration in winter is still poorly studied. Here we explored the different microbial characteristics and winter soil respiration in larch and Chinese pine plantation forests in northeastern China, which has similar climate and basic soil characteristics. Results showed that both mean and cumulative winter soil CO2 fluxes were significantly higher in Chinese pine forest (0.45 µmol m−2 s−1 and 46.39 g C m−2, respectively) than in larch forest (0.25 µmol m−2 s−1 and 25.92 g C m−2, respectively). Snow depth and inorganic nitrogen (N) could not explain the differences in winter soil respiration between the two sites. Instead, Chinese pine forest had higher soil microbial biomass, fungi abundance, F/B (ratio of fungi to bacteria), and extracellular enzymatic activities (EEAs) than larch forest, which could lead to higher winter soil respiration in Chinese pine forest than in larch forest. Our findings indicated that the thermal insulation effect of litter cover was important to winter soil respiration, especially when the snow cover depth was less than 30 cm. Soil microbes played a more important role in soil respiration than soil nutrient status and should be carefully considered for better estimation of the C budget in different forest ecosystems. Although soil respiration was higher in Chinese pine forest, soil organic C content was also higher, suggesting its better C sequestration capacity than larch forest.
Gap junctions (GJs), which are proteinaceous channels, couple adjacent cells by permitting direct exchange of intracellular molecules with low molecular weights. GJ intercellular communication (GJIC) ...plays a critical role in regulating behaviors of human embryonic stem cells (hESCs), affecting their proliferation and differentiation. Here we report a novel use of sonoporation that enables single cell intracellular dye loading and dynamic visualization/quantification of GJIC in hESC colonies. By applying a short ultrasound pulse to excite single microbubbles tethered to cell membranes, a transient pore on the cell membrane (sonoporation) is generated which allows intracellular loading of dye molecules and influx of Ca
into single hESCs. We employ live imaging for continuous visualization of intercellular dye transfer and Ca
diffusion in hESC colonies. We quantify cell-cell permeability based on dye diffusion using mass transport models. Our results reveal heterogeneous intercellular connectivity and a variety of spatiotemporal characteristics of intercellular Ca
waves in hESC colonies induced by sonoporation of single cells.
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