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A compression module system placed under a microscope was utilized to conduct uniaxial compression testing of sandstone samples. The test system can acquire the image of crack propagation on the specimen surface in real time. The focus of this study was to analyze how the motion of sandstone composition particles affect the failure mechanism of the samples under minimal loading rates. The results indicate that the load displacement curves align with the macroscopic failure laws under different loading rates. Furthermore, the lower the loading rate, the greater the deformation and crushing degree of sandstone during failure. The failure mode becomes more complex and gradually transitions from tension failure to shear-tension failure. The crack evolution of sandstone was caused by the uncoordinated movement of its components, and the weak structure induces cracks under the action of external load. Microcracks are initially generated at the interface between mineral particles and the sandstone matrix and propagate along the boundary between mineral and matrix. The interaction between component particles in sandstone leads to the connection break between particles which forms microcracks, and results in local deformation of the sample. The aggregation of multiple cracks leads to the instability and failure of sandstone. [ABSTRACT FROM AUTHOR]

Fibrosis is the progressive accumulation of excess extracellular matrix and can cause organ failure. Fibrosis can affect nearly every organ including kidney and there is no specific treatment currently. Although Epidermal Growth Factor Receptor (EGFR) signaling pathway has been implicated in development of kidney fibrosis, underlying mechanisms by which EGFR itself mediates kidney fibrosis have not been elucidated. We find that EGFR expression increases in interstitial myofibroblasts in human and mouse fibrotic kidneys. Selective EGFR deletion in the fibroblast/pericyte population inhibits interstitial fibrosis in response to unilateral ureteral obstruction, ischemia or nephrotoxins. In vivo and in vitro studies and single-nucleus RNA sequencing analysis demonstrate that EGFR activation does not induce myofibroblast transformation but is necessary for the initial pericyte/fibroblast migration and proliferation prior to subsequent myofibroblast transformation by TGF-ß or other profibrotic factors. These findings may also provide insight into development of fibrosis in other organs and in other conditions. Fibrosis is the progressive accumulation of excess extracellular matrix produced by myofibroblasts leading to organ failure. Here the authors show that expression of the Epidermal Growth Factor Receptor (EGFR) increases in interstitial myofibroblasts in human and mouse fibrotic kidneys, and selective EGFR deletion in the fibroblast/pericyte population inhibits interstitial fibrosis in response to unilateral ureteral obstruction, ischemia or nephrotoxins. [ABSTRACT FROM AUTHOR]

Obesity and obesity-related health complications are increasing in prevalence. Adipose tissue from obese subjects has low-grade, chronic inflammation, leading to insulin resistance. Adipose tissue macrophages (ATMs) are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction. In response to a high fat diet (HFD), ATM numbers initially increase by proliferation of resident macrophages, but subsequent increases also result from infiltration in response to chemotactic signals from inflamed adipose tissue. To elucidate the underlying mechanisms regulating the increases in ATMs and their proinflammatory phenotype, we investigated the role of activation of ATM epidermal growth factor receptor (EGFR). A high fat diet increased expression of EGFR and its ligand amphiregulin in ATMs. Selective deletion of EGFR in ATMs inhibited both resident ATM proliferation and monocyte infiltration into adipose tissue and decreased obesity and development of insulin resistance. Therefore, ATM EGFR activation plays an important role in adipose tissue dysfunction. In obesity, adipose tissue is chronically inflamed, leading to insulin resistance, and adipose tissue macrophages (ATMs) are a major source of cytokines that aggravate adipocyte dysfunction. Here, the authors show that selective deletion of the epidermal growth factor receptor in ATMs decreased obesity and development of insulin resistance. [ABSTRACT FROM AUTHOR]

In the present work, direct chiral separation of ofloxacin enantiomers was conducted using a Chiral MD (2) column as a chiral stationary phase (CSP) by a normal phase HPLC method, and then applied to enantiomeric quality control of two commercial pharmaceuticals containing the ofloxacin racemate and S-enantiomer, respectively. Experimental results indicated that the simultaneous addition of acid and alkaline additives to the mobile phase was important for improving the enantiomeric resolution. Combined with the molecular docking research, we found that the difference in the binding energy of each enantiomer interacting with CSP reached the maximum when the ofloxacin molecule was non-ionized. That is why both the acid and alkaline additives are necessary in the enantioseparation. Computer simulation results further revealed that hydrogen bonding, hydrophobic effects and π–π stacking were all involved in the stereoselective interaction, causing the difference in the binding strength with CSP, which eventually resulted in the chiral separation of the ofloxacin enantiomers. [ABSTRACT FROM AUTHOR]

In the present study, an accurate, rapid, and simple chiral HPLC‐UV method with amylose tris(3‐chloro‐5‐methylphenylcarbamate) as stationary phase was developed and applied for enantiomeric determination of six nonsteroidal anti‐inflammatory drugs (NSAIDs) in the commercial pharmaceutical formulations, including (R,S)‐ibuprofen, S‐ibuprofen, (R,S)‐ketoprofen, S‐ketoprofen, S‐naproxen, and (R,S)‐loxoprofen sodium. Experiments on the influence of mobile phase composition, proportion of organic modifier, percentage of acid additives, and column temperature on enantioseparation were conducted to obtain the best separation condition. It was indicated that one mobile phase simply composed of acetonitrile‐water (0.1% formic acid, v/v) at the proportion of 50:50 (v/v) with a flow rate of 0.6 ml/min at 22°C could simultaneously provide the excellent enantiomeric resolutions for all selected NSAIDs, which made the enantioseparation process more applicable and operable. The newly developed method was then applied for determination of NSAID enantiomers in pharmaceutical formulations containing racemic mixtures or single stereoisomers. Calibration curve of each enantiomer at the concentration of 5.0–100 ug/ml showed good linearity with the correlation coefficient above 0.9996. Satisfactory recovery (96.54–101.54%), good intra‐day precision (RSD 0.52–1.46%), and inter‐day precision (RSD 0.13–1.09%) were also obtained. The newly developed method was then applied for determination of NSAID enantiomers in pharmaceutical formulations containing racemic mixtures or single stereoisomers. Quantitative results of the commercial capsules and tablets demonstrated that the difference between the declared and measured values did not exceed 1.52%. [ABSTRACT FROM AUTHOR]

Podocyte injury is important in development of diabetic nephropathy (DN). Although several studies have reported single-cell-based RNA sequencing (RNA-seq) of podocytes in type 1 DN (T1DN), the podocyte translating mRNA profile in type 2 DN (T2DN) has not previously been compared with that of T1DN. We analyzed the podocyte translatome in T2DN in podocin-Cre; Rosa26fsTRAP; eNOS-/-; db/db mice and compared it with that of streptozotocin-induced T1DN in podocin-Cre; Rosa26fsTRAP; eNOS-/- mice using translating ribosome affinity purification (TRAP) and RNA-seq. More than 125 genes were highly enriched in the podocyte ribosome. More podocyte TRAP genes were differentially expressed in T2DN than in T1DN. TGF-β signaling pathway genes were upregulated, while MAPK pathway genes were downregulated only in T2DN, while ATP binding and cAMP-mediated signaling genes were downregulated only in T1DN. Genes regulating actin filament organization and apoptosis increased, while genes regulating VEGFR signaling and glomerular basement membrane components decreased in both type 1 and type 2 diabetic podocytes. A number of diabetes-induced genes not previously linked to podocyte injury were confirmed in both mouse and human DN. On the basis of differences and similarities in the podocyte translatome in T2DN and T1DN, investigators can identify factors underlying the pathophysiology of DN and novel therapeutic targets to treat diabetes-induced podocyte injury. [ABSTRACT FROM AUTHOR]

Renal epidermal growth factor receptor (EGFR) signaling is activated in models of diabetic nephropathy (DN), and inhibition of the EGFR signaling pathway protects against the development of DN. We have now determined that in cultured podocytes, high glucose led to increases in activation of EGFR signaling but decreases in autophagy activity as indicated by decreased beclin-1 and inhibition of LC3B autophagosome formation as well as increased rubicon (an autophagy inhibitor) and SQSTM1 (autophagy substrate). Either genetic (small interfering [si]EGFR) or pharmacologic (AG1478) inhibition of EGFR signaling attenuated the decreased autophagy activity. In addition, rubicon siRNA knockdown prevented high glucose-induced inhibition of autophagy in podocytes. We further examined whether selective EGFR deletion in podocytes affected the progression of DN in type 2 diabetes. Selective podocyte EGFR deletion had no effect on body weight or fasting blood sugars in either db/db mice or nos3-/-; db/db mice, a model of accelerated type 2 DN. However selective podocyte EGFR deletion led to relative podocyte preservation and marked reduction in albuminuria and glomerulosclerosis, renal proinflammatory cytokine/chemokine expression, and decreased profibrotic and fibrotic components in nos3-/-; db/db mice. Podocyte EGFR deletion led to decreased podocyte expression of rubicon, in association with increased podocyte autophagy activity. Therefore, activation of EGFR signaling in podocytes contributes to progression of DN at least in part by increasing rubicon expression, leading to subsequent autophagy inhibition and podocyte injury. [ABSTRACT FROM AUTHOR]

Featured Application: This study can provide guidance for coal and coalbed methane mining processes in multi-layered coal seams. Coalbed methane is not only a clean energy source, but also a major problem affecting the efficient production of coal mines. Hydraulic fracturing is an effective technology for enhancing the coal seam permeability to achieve the efficient extraction of methane. This study investigated the effect of a coal seam reservoir's geological factors on the initiation pressure and fracture propagation. Through theoretical analysis, a multi-layered coal seam initiation pressure calculation model was established based on the broken failure criterion of maximum tensile stress theory. Laboratory experiments were carried out to investigate the effects of the coal seam stress and coal seam dip angle on the crack initiation pressure and fracture propagation. The results reveal that the multi-layered coal seam hydraulic fracturing initiation pressure did not change with the coal seam inclination when the burial depth was the same. When the dip angle was the same, the initiation pressure linearly increased with the reservoir depth. A three-dimensional model was established to simulate the actual hydraulic fracturing crack propagation in multi-layered coal seams. The results reveal that the hydraulic crack propagated along the direction of the maximum principal stress and opened in the direction of the minimum principal stress. As the burial depth of the reservoir increased, the width of the hydraulic crack also increased. This study can provide the theoretical foundation for the effective implementation of hydraulic fracturing in multi-layered coal seams. [ABSTRACT FROM AUTHOR]

Purpose: Vitamin K deficiency, expressed by a high level of desphospho-uncarboxylated matrix GLA protein (dp-ucMGP), is highly prevalent in dialysis patients. However, the predictive ability of the vitamin K status remains unclear in continuous ambulatory peritoneal dialysis (CAPD) patients.Methods: 158 prevalent CAPD patients with a median level of dp-ucMGP of 1093 (752, 1485) pmol/L were enrolled. Patient outcomes including all-cause mortality and cardiovascular events (CVEs) were recorded during follow-up. Survival curves were performed using Kaplan-Meier method, and the influences of dp-ucMGP on outcomes were analyzed by Cox regression models.Results: A total of 59 deaths and 82 new episodes of CVEs occurred during median follow-up of 31.4 ± 13.1 months (range: 3.8-48.0 months). Kaplan-Meier analysis revealed patients with higher dp-ucMGP levels (≥ 1093 pmol/L) had an increased risk for both mortality (P = 0.005) and CVEs (P < 0.001). Multivariable Cox regression confirmed that higher dp-ucMGP levels increase the mortality risk [hazard ratio (HR), 1.763; 95% CI 1.045-3.291] and CVEs (HR, 1.846; 95% CI 1.074-3.172). For every 100 pmol/L increase in serum dp-ucMGP, the adjusted HRs for mortality and CVEs were 1.054 (95% CI 1.008-1.106) and 1.034 (95% CI 1.012-1.089), respectively.Conclusions: Vitamin K deficiency, as expressed by high dp-ucMGP levels, showed independently associations with mortality and CVEs in CAPD patients. [ABSTRACT FROM AUTHOR]

Increased high mobility group box 1 (HMGB1) in dialysis effluence is associated with the presence of peritoneal dialysis-related peritonitis in patients and peritoneal dysfunction in acute peritonitis mice model, but it remains unclear whether HMGB1 is involved in peritoneal mesothelial cell injury and functions via molecular posttranslational modifications by acetylation in this process. Here we first showed correlation between HMGB1 acetylation level in dialysis effluence of patients and occurrence of Gram-negative peritonitis. The increased level of acetylated HMGB1 was similarly observed under the lipopolysaccharides (LPS) treatment in both human peritoneal mesothelial cell line (HMrSV5) and mice visceral peritoneum tissue. Overexpression of wild-type, but not hypoacetylation mutant of HMGB1, enhanced LPS-induced apoptosis in HMrSV5 cells, which was accompanied by elevated protein levels of BAX and cleaved-caspase 3 compared to the control. Pretreatment of HMrSV5 cell with JNK inhibitor attenuated LPS-induced HMGB1 acetylation. Consistently, primary peritoneal mesothelial cells from Jnk1-/- mice showed a lower protein contents of acetylated HMGB1, fewer apoptosis, and decreased protein expression of BAX and cleaved-caspase3 after LPS exposure, as compared to those from wild-type mice. In conclusion, our data demonstrated HMGB1 promotes LPS-induced peritoneal mesothelial cells apoptosis, which is associated with JNK1-mediated upregulation of HMGB1 acetylation. [ABSTRACT FROM AUTHOR]

Inadequate potassium (K+) consumption correlates with increased mortality and poor cardiovascular outcomes. Potassium effects on blood pressure have been described previously; however, whether or not low K+ independently affects kidney disease progression remains unclear. Here, we demonstrate that dietary K+ deficiency causes direct kidney injury. Effects depend on reduced blood K+ and are kidney specific. In response to reduced K+, the channel Kir4.2 mediates altered proximal tubule (PT) basolateral K+ flux, causing intracellular acidosis and activation of the enzyme glutaminase and the ammoniagenesis pathway. Deletion of either Kir4.2 or glutaminase protects from low-K+ injury. Reduced K+ also mediates injury and fibrosis in a model of aldosteronism. These results demonstrate that the PT epithelium, like the distal nephron, is K+ sensitive, with reduced blood K+ causing direct PT injury. Kir4.2 and glutaminase are essential mediators of this injury process, and we identify their potential for future targeting in the treatment of chronic kidney disease. [Display omitted] • K+ deficiency causes kidney-specific injury and inflammation • Injury effects are dependent on the proximal K+ channel Kir4.2 • Kir4.2 mediates activation of the ammoniagenesis pathway under low-K+ conditions • Kidney deletion of glutaminase prevents low-K+-mediated kidney injury Terker et al. demonstrate that dietary K+ deficiency causes kidney-specific injury and inflammation. Effects are mediated by the proximal tubule basolateral K+ channel Kir4.2, which promotes ammoniagenesis in response to reduced blood K+ levels. Deletion of this channel or the enzyme glutaminase protect animals from low-K+-mediated kidney injury. [ABSTRACT FROM AUTHOR]

Background: Abnormal serum potassium is associated with an increased risk of mortality in dialysis patients. However, the impacts of serum potassium levels on short- and long-term mortality and association of potassium variability with death in peritoneal dialysis (PD) patients are uncertain. Methods: We examined mortality-predictability of serum potassium at baseline and its variability in PD patients treated in our center January 2006 through December 2010 with follow-up through December 2012. The hazard ratios (HRs) were used to assess the relationship between baseline potassium levels and short-term (≤1 year) as well as long-term (>1 year) survival. Variability of serum potassium was defined as the coefficient of variation of serum potassium (CVSP) during the first year of PD. Results: A total of 886 incident PD patients were enrolled, with 248 patients (27.9%) presented hypokalemia (serum potassium <3.5 mEq/L). During a median follow-up of 31 months (range: 0.5–81.0 months), adjusted all-cause mortality hazard ratio (HR) and 95% confidence interval (CI) for baseline serum potassium of <3.0, 3.0 to <3.5, 3.5 to <4.0, 4.5 to <5.0, and ≥5.0 mEq/L, compared with 4.0 to <4.5 (reference), were 1.79 (1.02–3.14), 1.15 (0.72–1.86), 1.31 (0.82–2.08), 1.33 (0.71–2.48), 1.28 (0.53–3.10), respectively. The increased risk of lower potassium with mortality was evident during the first year of follow-up, but vanished thereafter. Adjusted all-cause mortality HR for CVSP increments of 7.5% to <12.0%; 12.0% to <16.7% and ≥16.7%, compared with <7.5% (reference), were 1.35 (0.67–2.71), 2.00 (1.05–3.83) and 2.18 (1.18–4.05), respectively. Similar association was found between serum potassium levels and its variability and cardiovascular mortality. Conclusions: A lower serum potassium level was associated with all-cause and cardiovascular mortality during the first year of follow-up in incident PD patients. In addition, higher variability of serum potassium levels conferred an increased risk of death in this population. [ABSTRACT FROM AUTHOR]