Cyclic GMP-AMP synthase (cGAS) senses cytosolic incoming DNA and consequently activates stimulator of interferon response cGAMP interactor 1 (STING) to mount immune response. Here, we show nuclear ...cGAS could regulate VEGF-A-mediated angiogenesis in an immune-independent manner. We found VEGF-A stimulation induces cGAS nuclear translocation via importin-β pathway. Moreover, nuclear cGAS subsequently regulates miR-212-5p-ARPC3 cascade to modulate VEGF-A-mediated angiogenesis through affecting cytoskeletal dynamics and VEGFR2 trafficking from trans-Golgi network (TGN) to plasma membrane via a regulatory feedback loop. In contrast, cGAS deficiency remarkably impairs VEGF-A-mediated angiogenesis in vivo and in vitro. Furthermore, we found strong association between the expression of nuclear cGAS and VEGF-A, and the malignancy and prognosis in malignant glioma, suggesting that nuclear cGAS might play important roles in human pathology. Collectively, our findings illustrated the function of cGAS in angiogenesis other than immune surveillance, which might be a potential therapeutic target for pathological angiogenesis-related diseases.
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•VEGF-A stimulation induces cGAS nuclear translocation via importin-β pathway•Nuclear cGAS modulates VEGF-A-mediated angiogenesis via regulating miR-212-5p-ARPC3 cascade•cGAS loss impairs trans-Golgi network-involved VEGFR2 trafficking•Nuclear translocation of cGAS is associated with human pathology
Luo et al. illustrated the roles of nuclear cGAS in VEGF-A-mediated angiogenesis in vivo and in vitro. Nuclear cGAS is essential for VEGF-A-induced angiogenesis through affecting cell migration, cytoskeleton rearrangements, and VEGFR2 trafficking, which might contribute to the treatment of pathological angiogenesis-related diseases, such as cancer, and cardiovascular and eye diseases.
To develop light-weight polymer-based multifunctional materials with outstanding electromagnetic wave absorbing/shielding properties and high thermal conductivity, 2D interlinked carbon fiber ...networks (2D ICFNs) were synthesized via direct pyrolysis of filter papers at 600–900 °C. The pyrolysis temperature (Tp) was controlled to modulate the porosity, defects, and the resulting properties of 2D ICFNs. Owing to the co-manipulation of defects and porosity, the 2D ICFNs formed under Tp = 900 °C exhibit a larger EABWmax/d (3.57 GHz/mm) and stronger absorption (−44.66 dB) at a lower load (15%) compared to most other carbon fiber (CF)-based materials. Their shielding effectiveness is beyond 20 dB over 2.0–18.0 GHz with a maximal value of 76.2 dB at 18 GHz, surpassing the minimum requirement (20 dB) for practical applications. Besides, the 2D ICFNs with moderate porosity and high graphitization bear a larger thermal conductivity (2.69–2.93 W/mK) at a lower filling ratio (20 wt%) in comparison to the majority of previously reported materials. This is primarily due to the shortened phonon/electron transfer paths, decreased phonon-interface/-defect scattering, and continuous paths for thermal transmission in the 2D ICFNs. Overall, it is believed that the 2D ICFNs can be one of the most promising multifunctional fillers for EM absorption applications.
Briefs2D interlinked carbon fiber networks were synthesized via direct pyrolysis of filter papers, exhibiting defect/porosity-co-manipulating high thermal conductivity, good electric insulation, and prominent EMI shielding/absorption. Display omitted
•Direct pyrolysis of filter papers for 2D interlinked carbon fiber networks.•Controlling pyrolysis temperature to modulate the porosity and defects.•Optimizing the thermal, electrical, and EMW absorbing/shielding properties.•Defects and porosity co-manipulating the prominent properties.
Fe-based bulk metallic glasses (BMGs) have attracted great attention due to their excellent soft magnetic properties and high fracture strength, but few applications have been materialized as ...structural materials because of their brittleness at room temperature. Here, we successfully synthesized an Fe39Ni39B14.2Si2.75P2.75Nb2.3 BMG which exhibits large plastic strain of 7.8%, high fracture strength of 3.35 GPa and excellent soft magnetic properties, i.e., rather high saturation flux density of 0.88 T, low coercive force of 0.7 A/m and high permeability of 20800. The results indicated that the mutual repulsion between ductility and strength could be renovated in the Fe-based BMGs by the rearrangement of atomic configurations through Ni addition. With proper combination of non-directional metal-metal bonds and directional metal-metalloid bonds, the mechanical properties of FeNi-based BMGs can be improved. Our studies provide a guideline in designing ductile FeNi-based BMGs with high strength, large GFA and excellent soft magnetic properties.
•Fe-based BMGs with excellent soft magnetic properties were prepared.•Fe-based BMGs with large plastic strain and good GFA were synthesized.•The relationship between bonding nature and plasticity was investigated.
To improve the energy harvesting efficiency of the piezoelectric device, a stack units-based structure was developed and verified. Factors such as stress distribution, load resistance, loads, and ...loading times influencing the piezoelectric properties were investigated using theoretical analysis and experimental tests. The results show that the unit number has a negative relationship with the generated energy and the stress distribution has no influence on the power generation of the piezoelectric unit array. However, with a small stress difference, units in a parallel connection can obtain high energy conversion efficiency. Additionally, loaded with the matched impedance of 275.0 kΩ at 10.0 kN and 10.0 Hz, the proposed device reached a maximum output power of 84.3 mW, which is enough to supply the low-power sensors. Moreover, the indoor load test illustrates that the electrical performance of the piezoelectric device was positively correlated with the simulated loads when loaded with matched resistance. Furthermore, the electrical property remained stable after the fatigue test of 100,000 cyclic loads. Subsequently, the field study confirmed that the developed piezoelectric device had novel piezoelectric properties with an open-circuit voltage of 190 V under an actual tire load, and the traffic parameters can be extracted from the voltage waveform.
Skeletal muscle is heterogeneous tissue, composed of fast-twitch fibers primarily relying on glycolysis and slow-twitch fibers primarily relying on oxidative phosphorylation. The relative expression ...and balance of glycolysis and oxidative phosphorylation in skeletal muscle are crucial for muscle growth and skeletal muscle metabolism. Here, we employed multi-omics approaches including transcriptomics, proteomics, phosphoproteomics, and metabolomics to unravel the role of circMYLK4, a differentially expressed circRNA in fast and slow-twitch muscle fibers, in muscle fiber metabolism. We discovered that circMYLK4 inhibits glycolysis and promotes mitochondrial oxidative phosphorylation. Mechanistically, circMYLK4 interacts with the voltage-gated calcium channel auxiliary subunit CACNA2D2, leading to the inhibition of Ca2+ release from the sarcoplasmic reticulum. The decrease in cytoplasmic Ca2+ concentration inhibits the expression of key enzymes, PHKB and PHKG1, involved in glycogen breakdown, thereby suppressing glycolysis. On the other hand, the increased fatty acid β-oxidation enhances the tricarboxylic acid cycle and mitochondrial oxidative phosphorylation. In general, circMYLK4 plays an indispensable role in maintaining the metabolic homeostasis of skeletal muscle.
Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Hematopoietic dysfunction accompanied by severe aGVHD, which may be caused by ...niche impairment, is a long-standing clinical problem. However, how the bone marrow (BM) niche is damaged in aGVHD hosts is poorly defined. To comprehensively address this question, we employed a haplo-MHC-matched transplantation aGVHD murine model and performed single-cell RNA sequencing of non-hematopoietic BM cells. Transcriptional analysis showed that BM mesenchymal stromal cells (BMSCs) were severely affected with a reduction in cell ratio, abnormal metabolism, compromised differentiation potential and defective hematopoietic supportive function, which were validated by functional assays. We found that ruxolitinib, a selective JAK1/2 inhibitor, ameliorated aGVHD-related hematopoietic dysfunction through direct effect on recipient BMSCs, resulting in improved proliferation ability, adipogenesis/osteogenesis potential, mitochondrial metabolism capacity and crosstalk with donor-derived hematopoietic stem/progenitor cells. By inhibiting the JAK2/STAT1 pathway, ruxolitinib maintained long-term improvement of aGVHD BMSC function. Additionally, ruxolitinib pretreatment in vitro primed BMSCs to better support donor-derived hematopoiesis in vivo. These observations in the murine model were validated in patient samples. Overall, our findings suggest that ruxolitinib can directly restore BMSC function via JAK2/STAT1 pathway and in turn, improve the hematopoietic dysfunction caused by aGVHD.
Skeletal muscle is composed of muscle fibers with different physiological characteristics, which plays an important role in regulating skeletal muscle metabolism, movement and body homeostasis. The ...type of skeletal muscle fiber directly affects meat quality. However, the transcriptome and gene interactions between different types of muscle fibers are not well understood.
In this paper, we selected 180-days-old Large White pigs and found that longissimus dorsi (LD) muscle was dominated by fast-fermenting myofibrils and soleus (SOL) muscle was dominated by slow-oxidizing myofibrils by frozen sections and related mRNA and protein assays. Here, we selected LD muscle and SOL muscle for transcriptomic sequencing, and identified 312 differentially expressed mRNA (DEmRs), 30 differentially expressed miRNA (DEmiRs), 183 differentially expressed lncRNA (DElRs), and 3417 differentially expressed circRNA (DEcRs). The ceRNA network included ssc-miR-378, ssc-miR-378b-3p, ssc-miR-24-3p, XR_308817, XR_308823, SMIM8, MAVS and FOS as multiple core nodes that play important roles in muscle development. Moreover, we found that different members of the miR-10 family expressed differently in oxidized and glycolytic muscle fibers, among which miR-10a-5p was highly expressed in glycolytic muscle fibers (LD) and could target MYBPH gene mRNA. Therefore, we speculate that miR-10a-5p may be involved in the transformation of muscle fiber types by targeting the MYHBP gene. In addition, PPI analysis of differentially expressed mRNA genes showed that ACTC1, ACTG2 and ACTN2 gene had the highest node degree, suggesting that this gene may play a key role in the regulatory network of muscle fiber type determination.
We can conclude that these genes play a key role in regulating muscle fiber type transformation. Our study provides transcriptomic profiles and ceRNA interaction networks for different muscle fiber types in pigs, providing reference for the transformation of pig muscle fiber types and the improvement of meat quality.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Non-alcoholic fatty liver disease (NAFLD) is a common disease that causes serious liver damage. Exercise is recognized as a non-pharmacological tool to improve the pathology of NAFLD. However, the ...antioxidative effects and mechanisms by which exercise ameliorates NAFLD remain unclear. The present study conducted exercise training on zebrafish during a 12-week high-fat feeding period to study the antioxidant effect of exercise on the liver. We found that swimming exercise decreased lipid accumulation and improved pathological changes in the liver of high-fat diet-fed zebrafish. Moreover, swimming alleviated NOX4-derived reactive oxygen species (ROS) overproduction and reduced methanedicarboxylic aldehyde (MDA) levels. We also examined the anti-apoptotic effects of swimming and found that it increased the expression of antiapoptotic factor
and decreased the expression of genes associated with apoptosis (
,
). Mechanistically, swimming intervention activated SIRT1/AMPK signaling-mediated lipid metabolism and inflammation as well as enhanced AKT and NRF2 activation and upregulated downstream antioxidant genes. In summary, exercise attenuates pathological changes in the liver induced by high-fat diets. The underlying mechanisms might be related to NRF2 and mediated by SIRT1/AMPK signaling.
Aqueous zinc ion hybrid supercapacitors (ZHSCs) are receiving increasing research interest because of their superiority in safety, economy, and high water compatibility. However, the corrosion ...problems coupled with dendrite growth in an aqueous system severely limit the potential use of zinc storage systems with long service life. To delicately address the above obstacles, a κ-carrageenan/polyacrylamide/Zn(CF
3
SO
3
)
2
hydrogel electrolyte (denoted as κ-CG/PAAm/Zn(CF
3
SO
3
)
2
) with an ionically and covalently double crosslinked network was constructed, which possesses a high ionic conductivity of 2.3 S m
−1
, a high tensile strength of 34.6 kPa with a superior stretchability of 599.0%, and an excellent compression strength of 75.3 kPa at 75.0% strain. The double crosslinked polymer chains realize uniform zinc deposition. In addition, the intrinsic hydrophilic groups in the κ-carrageenan (κ-CG) and polyacrylamide (PAAm) chains can well immobilize water molecules, which favor electrolyte ion transport. Moreover, nitrogen and sulphur co-doped carbon nanosheets (denoted as ACNS) characterized by the rich amorphous phase associated with lots of short-range ordered microcrystalline regions were prepared as the cathode material in this work, which exhibits a high capacity of 116.4 mA h g
−1
coupled with superior rate performance and long-term cycling stability (108.0% capacity retention over 10 000 cycles) for an aqueous Zn//ACNS ZHSC. A quasi-solid-state ZHSC based on ACNS and κ-CG/PAAm/Zn(CF
3
SO
3
)
2
exhibits a specific capacity of 100.5 mA h g
−1
at 0.25 A g
−1
with a high capacity retention of 50.8% at 20 A g
−1
. The as-fabricated ZHSC also shows excellent cycling stability of 10 000 cycles as well as a superior energy density of 86.5 W h kg
−1
at a power density of 215.3 W kg
−1
. The ZHSC can also be used as a reliable source to drive various kinds of electronics (
e.g.
, mobile phones and electronic timers), which uncovers a feasible strategy for engineering the high-performance hydrogel electrolytes and cathode materials for ZHSC applications.
A κ-CG/PAAm/Zn(CF
3
SO
3
)
2
hydrogel electrolyte was constructed, which displays high ionic conductivity and satisfactory mechanical properties. The quasi-solid-state ZHSC based on ACNS and the as-designed hydrogel shows excellent cycling stability and a superior energy density.
Background: in current clinical practice, the standard evaluation for axillary lymph node (ALN) status in breast cancer has a low efficiency and is based on an invasive procedure that causes ...operative-associated complications in many patients. Therefore, we aimed to use machine learning techniques to develop an efficient preoperative magnetic resonance imaging (MRI) radiomics evaluation approach of ALN status and explore the association between radiomics and the tumor microenvironment in patients with early-stage invasive breast cancer.
Methods: in this retrospective multicenter study, three independent cohorts of patients with breast cancer (n = 1,088) were used to develop and validate signatures predictive of ALN status. After applying the machine learning random forest algorithm to select the key preoperative MRI radiomic features, we used ALN and tumor radiomic features to develop the ALN-tumor radiomic signature for ALN status prediction by the support vector machine algorithm in 803 patients with breast cancer from Sun Yat-sen Memorial Hospital and Sun Yat-sen University Cancer Center (training cohort). By combining ALN and tumor radiomic features with corresponding clinicopathologic information, the multiomic signature was constructed in the training cohort. Next, the external validation cohort (n = 179) of patients from Shunde Hospital of Southern Medical University and Tungwah Hospital of Sun Yat-Sen University, and the prospective-retrospective validation cohort (n = 106) of patients treated with neoadjuvant chemotherapy in prospective phase 3 trials NCT01503905, were included to evaluate the predictive value of the two signatures, and their predictive performance was assessed by the area under operating characteristic curve (AUC). This study was registered with ClinicalTrials.gov, number NCT04003558.
Findings: the ALN-tumor radiomic signature for ALN status prediction comprising ALN and tumor radiomic features showed a high prediction quality with AUC of 0·88 in the training cohort, 0·87 in the external validation cohort, and 0·87 in the prospective-retrospective validation cohort. The multiomic signature incorporating tumor and lymph node MRI radiomics, clinical and pathologic characteristics, and molecular subtypes achieved better performance for ALN status prediction with AUCs of 0·90, 0·91, and 0·93 in the training cohort, the external validation cohort, and the prospective-retrospective validation cohort, respectively. Among patients who underwent neoadjuvant chemotherapy in the prospective-retrospective validation cohort, there were significant differences in the key radiomic features before and after neoadjuvant chemotherapy, especially in the gray-level dependence matrix features. Furthermore, there was an association between MRI radiomics and tumor microenvironment features including immune cells, long non-coding RNAs, and types of methylated sites.
Interpretation this study presented a multiomic signature that could be preoperatively and conveniently used for identifying patients with ALN metastasis in early-stage invasive breast cancer. The multiomic signature exhibited powerful predictive ability and showed the prospect of extended application to tailor surgical management. Besides, significant changes in key radiomic features after neoadjuvant chemotherapy may be explained by changes in the tumor microenvironment, and the association between MRI radiomic features and tumor microenvironment features may reveal the potential biological underpinning of MRI radiomics.
No funding.
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