Interbedded rock layers are a typical geological structure in coal measures. In underground mining practices, the disturbance resulting from the extraction of long-wall panels changes the loading ...rate of roof–coal structures. To investigate the mechanical behavior and failure characteristics of roof–coal structures under different loading rates, composite coal–rock specimens with a height ratio of 1:1 was prepared and loaded under uniaxial compressive conditions with different loading rates. Acoustic emission signals and the deformation process of sandstone and coal were monitored. The fracture morphology was analyzed by scanning electron microscope (SEM), and the mean diameter of debris (da) was calculated to quantitatively evaluate the fragmentation. It is found that the sensitivity of the mechanical behavior to heterogeneity tends to decrease with the loading rate. The higher the loading rate, the less likely localized failure occurs in the pre-peak stage, the smoother the axial stress–axial strain curves before peak stress, and the greater the uniaxial compressive strength and Young’s modulus. The higher the loading rate, the more brittle the post-peak behavior and the severer the damage of the coal sample at the final loading stage. The coal sample tends to fail through intragranular cracking under a high load rate and intergranular cracking under a low loading rate. The sandstone sample exhibits deformation rebounding in the post-peak stage, providing direct evidence of energy transition from strain energy stored in the sandstone to cracking energy of the coal sample during coal failure. The higher the loading rate, the greater the rebounding speed of the sandstone, leading to severer damage to the coal sample.
Inflammation, cardiac remodeling, and fibrosis may explain in part the excess risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Growth differentiation factor 15 ...(GDF-15), galectin 3 (Gal-3), and soluble ST2 (sST2) are possible biomarkers of these pathways in patients with CKD.
Observational cohort study.
Individuals with CKD enrolled in either of 2 multicenter CKD cohort studies: the Seattle Kidney Study or C-PROBE (Clinical Phenotyping and Resource Biobank Study).
Circulating GDF-15, Gal-3, and sST2 measured at baseline.
Primary outcome was all-cause mortality. Secondary outcomes included hospitalization for physician-adjudicated heart failure and the atherosclerotic CVD events of myocardial infarction and cerebrovascular accident.
Cox proportional hazards models used to test the association of each biomarker with each outcome, adjusting for demographics, CVD risk factors, and kidney function.
Among 883 participants, mean estimated glomerular filtration rate was 49±19mL/min/1.73m2. Higher GDF-15 (adjusted HR aHR per 1-SD higher, 1.87; 95% CI, 1.53-2.29), Gal-3 (aHR per 1-SD higher, 1.51; 95% CI, 1.36-1.78), and sST2 (aHR per 1-SD higher, 1.36; 95% CI, 1.17-1.58) concentrations were significantly associated with mortality. Only GDF-15 level was also associated with heart failure events (HR per 1-SD higher, 1.56; 95% CI, 1.12-2.16). There were no detectable associations between GDF-15, Gal-3, or sST2 concentrations and atherosclerotic CVD events.
Event rates for heart failure and atherosclerotic CVD were low.
Adults with CKD and higher circulating GDF-15, Gal-3, and sST2 concentrations experienced greater mortality. Elevated GDF-15 concentration was also associated with an increased rate of heart failure. Further work is needed to elucidate the mechanisms linking these circulating biomarkers with CVD in patients with CKD.
The post-peak characteristics of coal serve as a direct reflection of its failure process and are essential parameters for evaluating brittleness and bursting liability. Understanding the significant ...factors that influence post-peak characteristics can offer valuable insights for the prevention of coal bursts. In this study, the Synthetic Rock Mass method is employed to establish a numerical model, and the factors affecting coal post-peak characteristics are analyzed from four perspectives: coal matrix mechanical parameters, structural weak surface properties, height-to-width ratio, and loading rate. The research identifies four significant influencing factors: deformation modulus, density of discrete fracture networks, height-to-width ratio, and loading rate. The response and sensitivity of post-peak characteristics to single-factor and multi-factor interactions are assessed. The result suggested that feasible prevention and control measures for coal bursts can be formulated through four approaches: weakening the mechanical properties of coal pillars, increasing the number of structural weak surfaces in coal pillars, reducing the width of coal pillars, and optimizing mining and excavation speed. The efficacy of measures aimed at weakening the mechanical properties of coal is successfully demonstrated through a case study on coal burst prevention using large-diameter borehole drilling.
Growth differentiation factor-15 (GDF-15) is a member of the TGF-
cytokine superfamily that is widely expressed and may be induced in response to tissue injury. Elevations in GDF-15 may identify a ...novel pathway involved in loss of kidney function among patients with CKD. Among participants in the Clinical Phenotyping and Resource Biobank (C-PROBE) study and the Seattle Kidney Study (SKS), we tested whether kidney tissue expression of
mRNA correlates with circulating levels of GDF-15 and whether elevations in circulating GDF-15 are associated with decline in kidney function. In matching samples of 24 patients with CKD from the C-PROBE study, circulating GDF-15 levels significantly correlated with intrarenal
transcript levels (
=0.54,
=0.01). Among the 224 C-PROBE and 297 SKS participants, 72 (32.1%) and 94 (32.0%) patients, respectively, reached a composite end point of 30% decline in eGFR or progression to ESRD over a median of 1.8 and 2.0 years of follow up, respectively. In multivariable models, after adjusting for potential confounders, every doubling of GDF-15 level associated with a 72% higher (95% confidence interval, 1.21 to 4.45;
=0.003) and 65% higher (95% confidence interval, 1.08 to 2.50;
=0.02) risk of progression of kidney disease in C-PROBE and SKS participants, respectively. These results show that circulating GDF-15 levels strongly correlated with intrarenal expression of
and significantly associated with increased risk of CKD progression in two independent cohorts. Circulating GDF-15 may be a marker for intrarenal
-related signaling pathways associated with CKD and CKD progression.
Type I CRISPR-Cas systems employ multi-subunit effector Cascade and helicase-nuclease Cas3 to target and degrade foreign nucleic acids, representing the most abundant RNA-guided adaptive immune ...systems in prokaryotes. Their ability to cause long fragment deletions have led to increasing interests in eukaryotic genome editing. While the Cascade structures of all other six type I systems have been determined, the structure of the most evolutionarily conserved type I-B Cascade is still missing. Here, we present two cryo-EM structures of the Synechocystis sp. PCC 6714 (Syn) type I-B Cascade, revealing the molecular mechanisms that underlie RNA-directed Cascade assembly, target DNA recognition, and local conformational changes of the effector complex upon R-loop formation. Remarkably, a loop of Cas5 directly intercalated into the major groove of the PAM and facilitated PAM recognition. We further characterized the genome editing profiles of this I-B Cascade-Cas3 in human CD3
T cells using mRNA-mediated delivery, which led to unidirectional 4.5 kb deletion in TRAC locus and achieved an editing efficiency up to 41.2%. Our study provides the structural basis for understanding target DNA recognition by type I-B Cascade and lays foundation for harnessing this system for long range genome editing in human T cells.
•Ignoring strain softening and dilatancy will induce significant errors.•Considering dilatancy without strain softening has little influence on calculation.•Considering dilatancy can accelerate ...strain softening process.•Strain softening and dilatancy create a significant synergistic effect.•A rock bolting system can inhibit strain softening and dilatancy.
The extent of the plastic zone of the surrounding rock of a deep tunnel is significantly greater than that of a shallow tunnel, giving importance to correctly determine the post-peak mechanical behavior during a deep tunnel analysis. In this study, the nonlinearity of strain softening and dependence on the confining stress and plastic shear strain of the dilation angle were considered. Based on the incremental equations of the theory of plastic flow in FLAC3D, the influences of the strain softening and dilatancy on a deep tunnel analysis were discussed, and the modified M−C model was used in the numerical simulations for verification and further analysis. The results indicate that the extent of the plastic zone and the surface displacement of the surrounding rock are unrealistically small when the strain softening and dilatancy are ignored. When considering only strain softening, the plastic zone and surface displacement increase significantly. When considering only the dilatancy, the extent of the plastic zone exhibits no change, and the surface displacement increases only slightly. The increase in dilation angle will lead to an acceleration of the strain softening process, that is, a decrease in the strength of the rock mass occurs. There is a significant synergistic effect of the strain softening and dilatancy, that is, the influence of considering the two factors together is greater than the sum of considering the two factors individually. A rock bolting system can improve the residual strength of the surrounding rock of a deep tunnel, strengthen the confinement of the shallow to deep parts of the surrounding rock, reduce the level of strain softening and the dilation angle, and thus, significantly reduce the extent of the plastic zone and surface displacement of the surrounding rock. Therefore, a tunnel should be supported in time after an excavation to prevent a degradation of the surrounding rock and make full use of the self-support capacity of the surrounding rock. When a numerical simulation is applied to the deformation prediction and the support design of a deep tunnel, the accurate strain softening and dilatancy should be considered simultaneously.
Smad2 and Smad3 interact and mediate TGF-beta signaling. Although Smad3 promotes fibrosis, the role of Smad2 in fibrogenesis is largely unknown. In this study, conditional deletion of Smad2 from the ...kidney tubular epithelial cells markedly enhanced fibrosis in response to unilateral ureteral obstruction. In vitro, Smad2 knockdown in tubular epithelial cells increased expression of collagen I, collagen III, and TIMP-1 and decreased expression of the matrix-degrading enzyme MMP-2 in response to TGF-beta1 compared with similarly treated wild-type cells. We obtained similar results in Smad2-knockout fibroblasts. Mechanistically, Smad2 deletion promoted fibrosis through enhanced TGF-beta/Smad3 signaling, evidenced by greater Smad3 phosphorylation, nuclear translocation, promoter activity, and binding of Smad3 to a collagen promoter (COL1A2). Moreover, deletion of Smad2 increased autoinduction of TGF-beta1. Conversely, overexpression of Smad2 attenuated TGF-beta1-induced Smad3 phosphorylation and collagen I matrix expression in tubular epithelial cells. In conclusion, in contrast to Smad3, Smad2 protects against TGF-beta-mediated fibrosis by counteracting TGF-beta/Smad3 signaling.
Cell-lineage-specific transcripts are essential for differentiated tissue function, implicated in hereditary organ failure, and mediate acquired chronic diseases. However, experimental identification ...of cell-lineage-specific genes in a genome-scale manner is infeasible for most solid human tissues. We developed the first genome-scale method to identify genes with cell-lineage-specific expression, even in lineages not separable by experimental microdissection. Our machine-learning-based approach leverages high-throughput data from tissue homogenates in a novel iterative statistical framework. We applied this method to chronic kidney disease and identified transcripts specific to podocytes, key cells in the glomerular filter responsible for hereditary and most acquired glomerular kidney disease. In a systematic evaluation of our predictions by immunohistochemistry, our in silico approach was significantly more accurate (65% accuracy in human) than predictions based on direct measurement of in vivo fluorescence-tagged murine podocytes (23%). Our method identified genes implicated as causal in hereditary glomerular disease and involved in molecular pathways of acquired and chronic renal diseases. Furthermore, based on expression analysis of human kidney disease biopsies, we demonstrated that expression of the podocyte genes identified by our approach is significantly related to the degree of renal impairment in patients. Our approach is broadly applicable to define lineage specificity in both cell physiology and human disease contexts. We provide a user-friendly website that enables researchers to apply this method to any cell-lineage or tissue of interest. Identified cell-lineage-specific transcripts are expected to play essential tissue-specific roles in organogenesis and disease and can provide starting points for the development of organ-specific diagnostics and therapies.
Chronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of ...underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify metabolic pathways that are altered in adults with non-diabetic stage 3–4 CKD versus healthy adults. Urinary excretion rate of 27 metabolites and plasma concentration of 33 metabolites differed significantly in CKD patients versus controls (estimate range−68% to +113%). Pathway analysis revealed that the citric acid cycle was the most significantly affected, with urinary excretion of citrate, cis-aconitate, isocitrate, 2-oxoglutarate and succinate reduced by 40–68%. Reduction of the citric acid cycle metabolites in urine was replicated in an independent cohort. Expression of genes regulating aconitate, isocitrate, 2-oxoglutarate and succinate were significantly reduced in kidney biopsies. We observed increased urine citrate excretion (+74%, p=0.00009) and plasma 2-oxoglutarate concentrations (+12%, p=0.002) in CKD patients during treatment with a vitamin-D receptor agonist in a randomized trial. In conclusion, urinary excretion of citric acid cycle metabolites and renal expression of genes regulating these metabolites were reduced in non-diabetic CKD. This supports the emerging view of CKD as a state of mitochondrial dysfunction.
•Urinary excretion rate and plasma concentration of 60 metabolites differed significantly in CKD patients versus controls.•Pathway analysis revealed that the citric acid cycle was the most significantly affected.•Expression of genes regulating TCA cycle was significantly reduced in kidney biopsies.
Chronic kidney disease (CKD) is very common and carries a high risk of complications and death. Patients with advanced disease have severe fatigue, organ dysfunction beyond the kidneys, and disturbances in sugar, protein and fat metabolism. We found many metabolites that differed significantly in kidney patients versus healthy controls. Analysis revealed that the citric acid cycle was the most significantly affected metabolic pathway. The citric acid cycle is performed in the cells` mitochondria and is the central metabolic hub where fuel molecules are converted into energy. This supports the view of CKD as a state of mitochondrial dysfunction.
Chronic kidney disease (CKD) is a public health problem driven by myofibroblast accumulation, leading to interstitial fibrosis. Heterogeneity is a recently recognized characteristic in kidney ...fibroblasts in CKD, but the role of different populations is still unclear. Here, we characterize a proinflammatory fibroblast population (named CXCL-iFibro), which corresponds to an early state of myofibroblast differentiation in CKD. We demonstrate that CXCL-iFibro co-localize with macrophages in the kidney and participate in their attraction, accumulation, and switch into FOLR2+ macrophages from early CKD stages on. In vitro, macrophages promote the switch of CXCL-iFibro into ECM-secreting myofibroblasts through a WNT/β-catenin-dependent pathway, thereby suggesting a reciprocal crosstalk between these populations of fibroblasts and macrophages. Finally, the detection of CXCL-iFibro at early stages of CKD is predictive of poor patient prognosis, which shows that the CXCL-iFibro population is an early player in CKD progression and demonstrates the clinical relevance of our findings.
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