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Cell senescence is accompanied by decreased nicotinamide adenine dinucleotide (NAD+) levels; however, whether exogenous NAD+ affects bone marrow-derived mesenchymal stem cells (BMSCs) senescence and the involved mechanisms is still unclear. Here, we find that exogenous NAD+ replenishment significantly postpones BMSC senescence induced by D-galactose (D-gal). It is also shown that exogenous NAD+ leads to increased intracellular NAD+ levels and reduced intracellular reactive oxygen species in senescent BMSCs here. Further investigation showed that exogenous NAD+ weakened BMSC senescence by increasing Sirtuin 1 (Sirt1) expression. Moreover, exogenous NAD+ reduced senescence-associated-β-galactosidase activity, and downregulated poly (ADP-ribose) polymerase 1 expression. In addition, the reduced expression of Sirt1 by small interfering RNA abolished the beneficial effects of exogenous NAD+ in terms of postponing BMSCs senescence induced by D-gal. Taken together, our results indicate that exogenous NAD+ could postpone D-gal-induced BMSC senescence through Sirt1 signaling, providing a potential method for obtaining high quality BMSCs to support their research and clinical application.

this paper studied the start-up of natural bio-film colonization under the conditions where wet-to-dry ratio was 1:6, hydraulic load was 0.8m3/m2·d, and water temperature was 10°C-15°C, it took 25d in total to become mature, after the success of bio-film colonization, the removal rate of COD and NH4+-N can be stabilized at 80%, and the removal rate of NH4+-N can reach 90% above. The microorganism was divided into the following stages during bio-film colonization: 1.Reversible adhesion of cell on the surface of the carrier, 2.Irreversible adhesion of cell on the surface of the carrier, 3.Division of cell adhering to the surface of the carrier and formation of microcolony adhering to the surface of the carrier, 4.Growth of microcolony adhering to the surface of the carrier to be mature bio-film with three-dimensional structure. The process of natural bio-film colonization can be judged comprehensively according to removal rate of NH4+-N and COD, effluent pH as well as color of microbial film.

Caprock is a water-saturated formation with a sufficient entry capillary pressure to prevent the upward migration of a buoyant fluid. When the entry capillary pressure of caprock is smaller than the pressure exerted by the buoyant CO2 plume, CO2 gradually penetrates into the caprock. The CO2 penetration depth into a caprock layer can be used to measure the caprock sealing efficiency and becomes the key issue to the assessment of caprock sealing efficiency. On the other hand, our numerical simulations on a caprock layer have revealed that a square root law for time and pore pressure exists for the CO2 penetration into the caprock layer. Based on this finding, this study proposes a simple approach to estimate the CO2 penetration depth into a caprock layer. This simple approach is initially developed to consider the speed of CO2 invading front. It explicitly expresses the penetration depth with pressuring time, pressure difference and pressure magnitude. This simple approach is then used to fit three sets of experimental data and good fittings are observed regardless of pressures, strengths of porous media, and pore fluids (water, hydrochloric acid, and carbonic acid). Finally, theoretical analyses are conducted to explore those factors affecting CO2 penetration depth. The effects of capillary pressure, gas sorption induced swelling, and fluid property are then included in this simple approach. These results show that this simple approach can predict the penetration depth into a caprock layer with sufficient accuracy, even if complicated interactions in penetration process are not explicitly expressed in this simple formula.

The characteristics of urban green space have context-dependent associations with socioeconomic status (SES). Latin American cities provide a unique but understudied context to assess the green space-SES associations. We measured the quantity and quality of green space as greenness from satellite-derived Normalized Difference Vegetation Index, and we modeled the relationship between greenness and SES in 371 major Latin American cities between 2000 and 2015. We found that SES was negatively associated with average greenness at city and sub-city scales, which could be explained by urbanization generally improving SES while reducing the provision of green space. About 82% of the cities and 64% of the sub-cities experienced greening or increases in greenness over time. Although with lower average greenness, cities with higher SES had greater greening; however, it was the opposite for sub-cities. We suggest that greening is more likely to take place in peripheral sub-cities where SES tends to be lower. The findings challenge the belief that places with higher SES have better access to environmental resources and amenities; instead, this relationship is context dependent.

To investigate the relationship between the structural characteristics and seepage flow behavior of rough single rock fractures, a set of single fracture physical models were produced using the Weierstrass–Mandelbrot functions to test the seepage flow performance. Six single fractures, with various surface roughnesses characterized by fractal dimensions, were built using COMSOL multiphysics software. The fluid flow behavior through the rough fractures and the influences of the rough surfaces on the fluid flow behavior was then monitored. The numerical simulation indicates that there is a linear relationship between the average flow velocity over the entire flow path and the fractal dimension of the rough surface. It is shown that there is good a agreement between the numerical results and the experimental data in terms of the properties of the fluid flowing through the rough single rock fractures.

Bone marrow stromal cells (BMSCs, also broadly known as bone marrow-derived mesenchymal stem cells) are multipotent stem cells that have a self-renewal capacity and multilineage differentiation potential. Mechanical stretching plays a vital role in regulating the proliferation and differentiation of BMSCs. However, little is known about the effects of cyclic stretching on BMSC migration and invasion. In this study, using a custom-made cell-stretching device, we studied the effects of cyclic mechanical stretching on rat BMSC migration and invasion using a Transwell Boyden Chamber. The protein secretion of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) was detected by gelatin zymography, and the activation of focal adhesion kinase (FAK) and extracellular signal regulated kinase1/2 (ERK1/2) was measured by western blot. We found that cyclic mechanical stretching with 10% amplitude at 1 Hz frequency for 8 h promotes BMSC migration, but reduces BMSC invasion. FAK and ERK1/2 signals were activated in BMSCs after exposure to cyclic stretching. In the presence of the FAK phosphorylation blocker PF573228 or the ERK1/2 phosphorylation blocker PD98059, the cyclic-stretch-promoted migration of BMSCs was completely suppressed. On the other hand, cyclic mechanical stretching reduced the secretion of MMP-2 and MMP-9 in BMSCs, and PF573228 suppressed the cyclic-stretch-reduced secretion of MMP-2 and MMP-9. The decrease of BMSC invasion induced by mechanical stretching is partially restored by PF573228 but remained unaffected by PD98059. Taken together, these data show that cyclic mechanical stretching promotes BMSC migration via the FAK-ERK1/2 signalling pathway, but reduces BMSC invasion by decreasing secretion of MMP-2 and MMP-9 via FAK, independent of the ERK1/2 signal.

BACKGROUND AND AIMS: The change in hepatocellular carcinoma (HCC) care continuum during the coronavirus disease 2019 (COVID-19) pandemic remains unknown at a national level in the United States. We sought to determine the impact of the pandemic on incident HCC cases, clinical characteristics, and treatment in the United States. METHODS: Using the National Cancer Database, we analyzed incident HCC cases from 2010 to 2020. The incidence rate was calculated using the population data for each year from the census bureau. Joinpoint regression analysis was applied for trend analysis, and a polynomial regression model estimated the number of projected HCC cases in 2020 according to the trend of rates from 2010 to 2019. The distribution of cancer stage and treatment modality were assessed. RESULTS: The pandemic led to a significant reduction in reported HCC cases, from 19,597 in 2019 to 16,188 in 2020. The projected number of HCC for 2020 was 19,011, corresponding to a 14.8% reduction in 2020. Extent of reduction in the number of incident HCC cases relative to estimated cases remains consistent in racial and ethnic subgroups. Despite underdiagnosis of HCC in 2020, proportion of patients with early tumor stage (30.5% for Tumour, Node, Metastasis stage 1) and curative treatment receipt (9.1% for surgical resection, 13% for ablation, 4.2% for liver transplant) for HCC remained stable in the first year of the COVID-19 pandemic. CONCLUSION: There was a significant reduction in HCC cases in 2020 compared to pre-COVID years. While tumor stage and proportion of patients receiving curative treatment remained stable, continued follow-up is needed to assess potential changes during subsequent years.

Liver cancer remains a challenge of global health, being the 4th leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and is usually precipitated by chronic viral infections (hepatitis B and C), non-alcoholic steatohepatitis, heavy alcohol use, and other factors which may lead to chronic inflammation and cirrhosis of the liver. There have been significant advances in the systemic treatment options for HCC over the past decades, with several approvals of both immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with preserved liver function. These advances have led to improvement in survival outcomes, with expected survival of greater than 18 months, in those with sensitive tumors, adequate liver function, and those functionally fit to receive sequential therapies. Several ongoing and promising trials are now evaluating combinational strategies with novel systemic agents and combinations of systemic therapy with locoregional therapy. In view of these trials, further advances in the treatment of HCC are foreseen in the near future.

Background and aimsMagnetic resonance elastography (MRE) is an accurate, continuous biomarker of liver fibrosis; however, the optimal combination with clinical factors to predict the risk of incident hepatic decompensation is unknown. Therefore, we aimed to develop and validate an MRE-based prediction model for hepatic decompensation for patients with NAFLD.Approach and resultsThis international multicenter cohort study included participants with NAFLD undergoing MRE from 6 hospitals. A total of 1254 participants were randomly assigned as training (n = 627) and validation (n = 627) cohorts. The primary end point was hepatic decompensation, defined as the first occurrence of variceal hemorrhage, ascites, or HE. Covariates associated with hepatic decompensation on Cox-regression were combined with MRE to construct a risk prediction model in the training cohort and then tested in the validation cohort. The median (IQR) age and MRE values were 61 (18) years and 3.5 (2.5) kPa in the training cohort and 60 (20) years and 3.4 (2.5) kPa in the validation cohort, respectively. The MRE-based multivariable model that included age, MRE, albumin, aspartate aminotransferase, and platelets had excellent discrimination for the 3- and 5-year risk of hepatic decompensation (c-statistic 0.912 and 0.891, respectively) in the training cohort. The diagnostic accuracy remained consistent in the validation cohort with a c-statistic of 0.871 and 0.876 for hepatic decompensation at 3 and 5 years, respectively, and was superior to Fibrosis-4 in both cohorts ( p < 0.05).ConclusionsAn MRE-based prediction model allows for accurate prediction of hepatic decompensation and assists in the risk stratification of patients with NAFLD.

In this study, we successfully fabricated a single-crystal Fe2O3 nanowire array based on stress-induced atomic diffusion and used this array as the photoelectrode for solar water splitting. With the surface polishing treatment on the sample surface, the density of the Fe2O3 nanowire array reached up to 28.75 wire µm−2 when heated for 90 min at 600°C. The photocurrent density of the optimized sample was 0.9 mA cm−2 at 1.23 V versus a reversible hydrogen electrode in a three-electrode system under AM 1.5 G illumination. The incident photon-to-electron conversion efficiency was 6.8% at 400 nm.

Hydrofracturing technology of perforated horizontal well has been widely used to stimulate the tight hydrocarbon reservoirs for gas production. To predict the hydraulic fracture propagation, the microseismicity can be used to infer hydraulic fractures state; by the effective numerical methods, microseismic events can be addressed from changes of the computed stresses. In numerical models, due to the challenges in accurately representing the complex structure of naturally fractured reservoir, the interaction between hydraulic and pre-existing fractures has not yet been considered and handled satisfactorily. To overcome these challenges, the adaptive finite element-discrete element method is used to refine mesh, effectively identify the fractures propagation, and investigate microseismic modelling. Numerical models are composed of hydraulic fractures, pre-existing fractures, and microscale pores, and the seepage analysis based on the Darcy’s law is used to determine fluid flow; then moment tensors in microseismicity are computed based on the computed stresses. Unfractured and naturally fractured models are compared to assess the influences of pre-existing fractures on hydrofracturing. The damaged and contact slip events were detected by the magnitudes, B-values, Hudson source type plots, and focal spheres.

Mesenchymal stem cells (MSCs) are multilineage cells with the ability to self-renew and differentiate into a variety of cell types, which play key roles in tissue healing and regenerative medicine. Bone marrow-derived mesenchymal stem cells (BMSCs) are the most frequently used stem cells in cell therapy and tissue engineering. However, it is prerequisite for BMSCs to mobilize from bone marrow and migrate into injured tissues during the healing process, through peripheral circulation. The migration of BMSCs is regulated by mechanical and chemical factors in this trafficking process. In this paper, we review the effects of several main regulatory factors on BMSC migration and its underlying mechanism; discuss two critical roles of BMSCs—namely, directed differentiation and the paracrine function—in tissue repair; and provide insight into the relationship between BMSC migration and tissue repair, which may provide a better guide for clinical applications in tissue repair through the efficient regulation of BMSC migration.

One challenge in studying the second messenger inositol(1,4,5)-trisphosphate (InsP3) is that it is present in very low amounts and increases only transiently in response to stimuli. To identify events downstream of InsP3, we generated transgenic plants constitutively expressing the high specific activity, human phosphatidylinositol 4-phosphate 5-kinase Iα (HsPIPKIα). PIP5K is the enzyme that synthesizes phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2); this reaction is flux limiting in InsP3 biosynthesis in plants. Plasma membranes from transgenic Arabidopsis expressing HsPIPKIα had 2–3 fold higher PIP5K specific activity, and basal InsP3 levels in seedlings and leaves were >2-fold higher than wild type. Although there was no significant difference in photosynthetic electron transport, HsPIPKIα plants had significantly higher starch (2–4 fold) and 20% higher anthocyanin compared to controls. Starch content was higher both during the day and at the end of dark period. In addition, transcripts of genes involved in starch metabolism such as SEX1 (glucan water dikinase) and SEX4 (phosphoglucan phosphatase), DBE (debranching enzyme), MEX1 (maltose transporter), APL3 (ADP-glucose pyrophosphorylase) and glucose-6-phosphate transporter (Glc6PT) were up-regulated in the HsPIPKIα plants. Our results reveal that increasing the phosphoinositide (PI) pathway affects chloroplast carbon metabolism and suggest that InsP3 is one component of an inter-organelle signaling network regulating chloroplast metabolism.

Stem cells are undifferentiated cells that can give rise to any types of cells in our body. Hence, they have been utilized for various applications, such as drug testing and disease modeling. However, for the successful of those applications, the survival and differentiation of stem cells into specialized lineages should be well controlled. Growth factors and chemical agents are the most common signals to promote the proliferation and differentiation of stem cells. However, those approaches holds several drawbacks such as the negative side effects, degradation or denaturation, and expensive. To address such limitations, nanomaterials have been recently used as a better approach for controlling stem cells behaviors. Graphene oxide is the derivative of graphene, the first two-dimensional (2D) materials in the world. Recently, due to its extraordinary properties and great biological effects on stem cells, many scientists around the world have utilized graphene oxide to enhance the differentiation potential of stem cells. In this mini review, we highlight the key advances about the effects of graphene oxide on controlling stem cell growth and various types of stem cell differentiation. We also discuss the possible molecular mechanisms of graphene oxide in controlling stem cell growth and differentiation.

BackgroundThe purpose of this study was to determine the optimal dose of remifentanil for minimizing hemodynamic changes during intubation and reducing propofol-induced pain in elderly patients.MethodsIn a randomized prospective study, 60 patients (ASA I-II, elder than 65 years) were enrolled to determine which of two target remifentanil blood concentrations (3 ng/ml, 5 ng/ml) was required to blunt hemodynamic changes during intubation and to reduce propofol-induced pain. After the target effect site concentration of remifentanil had been reached, the target controlled infusion of propofol was started and propofol-induced pain was recorded. Blood pressure and heart rate were recorded at baseline, just before intubation and 1, 3, 5 min after intubation.ResultsThere were no significant differences in the hemodynamic parameters between two groups, but not in arterial pressure at just before intubation and 1 minute after intubation. However, the group R5 (5 ng/ml) showed significantly less intense pain induced by propofol than in the group R3 (3 ng/ml).ConclusionsThe results suggest that the group R5 provide more relief in propofol induced pain than the group R3, but showed great possibility of hypotension and bradycardia in both groups, which means it should be used with cautions in the elderly patients.

Root colonization by Pseudomonas chlororaphis O6 in cucumber elicited an induced systemic resistance (ISR) against Corynespora cassiicola. In order to gain insight into O6-mediated ISR, a suppressive subtractive hybridization technique was applied and resulted in the isolation of a cucumber galactinol synthase (CsGolS1) gene. The transcriptional level of CsGolS1 and the resultant galactinol content showed an increase several hours earlier under O6 treatment than in the water control plants following C. cassiicola challenge, whereas no difference was detected in the plants without a pathogen challenge. The CsGolS1-overexpressing transgenic tobacco plants demonstrated constitutive resistance against the pathogens Botrytis cinerea and Erwinia carotovora, and they also showed an increased accumulation in galactinol content. Pharmaceutical application of galactinol enhanced the resistance against pathogen infection and stimulated the accumulation of defense-related gene transcripts such as PR1a, PR1b, and NtACS1 in wild-type tobacco plants. Both the CsGolS1-overexpressing transgenic plants and the galactinol-treated wild-type tobacco plants also demonstrated an increased tolerance to drought and high salinity stresses.

BACKGROUND & AIMS: The extent to which nonalcoholic fatty liver disease (NAFLD) contributes to hepatocellular carcinoma (HCC) prevalence in contemporary practices and whether there are any etiologic differences in surveillance receipt, tumor stage, and overall survival (OS) remain unclear. We aimed to estimate the burden of NAFLD-related HCC and magnitude of associations with surveillance receipt, clinical presentation, and outcomes in a contemporary HCC cohort. METHODS: In a cohort of HCC patients from the Surveillance, Epidemiology and End Results-Medicare database between 2011 and 2015, we used multivariable logistic regression to identify factors associated with surveillance receipt, early-stage tumor detection, and curative treatment. Cox regression was used to identify factors associated with OS. RESULTS: Among 5098 HCC patients, NAFLD was the leading etiology, accounting for 1813 cases (35.6%). Compared with those with hepatitis C-related HCC, NAFLD was associated with lower HCC surveillance receipt (adjusted odds ratio, 0.22; 95% confidence interval [CI], 0.17-0.28), lower early-stage HCC detection (adjusted odds ratio, 0.49; 95% CI, 0.40-0.60), and modestly worse OS (adjusted hazard ratio, 1.20; 95% CI, 1.09-1.32). NAFLD subgroup analysis showed that early-stage HCC, absence of ascites/hepatic encephalopathy, surveillance, and curative treatment receipt were associated with improved OS. NAFLD patients with coexisting liver disease were more likely to have surveillance, early-stage detection, curative treatment, and improved OS than NAFLD patients without coexisting liver diseases. CONCLUSIONS: NAFLD is the leading etiology of HCC among Medicare beneficiaries. Compared with other etiologies, NAFLD was associated with lower HCC surveillance receipt, early-stage detection, and modestly poorer survival. Multifaceted interventions for improving surveillance uptake are needed to improve prognosis of patients with NAFLD-related HCC.

Background and aimsThe sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC.Approach and resultsTissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n  = 106) and an independent validation cohort ( n  = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99).ConclusionHCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

BackgroundPatients with cirrhosis and subcentimeter lesions on liver ultrasound are recommended to undergo short-interval follow-up ultrasound because of the presumed low risk of primary liver cancer (PLC).AimsThe aim of this study is to characterize recall patterns and risk of PLC in patients with subcentimeter liver lesions on ultrasound.MethodsWe conducted a multicenter retrospective cohort study among patients with cirrhosis or chronic hepatitis B infection who had subcentimeter ultrasound lesions between January 2017 and December 2019. We excluded patients with a history of PLC or concomitant lesions ≥1 cm in diameter. We used Kaplan Meier and multivariable Cox regression analyses to characterize time-to-PLC and factors associated with PLC, respectively.ResultsOf 746 eligible patients, most (66.0%) had a single observation, and the median diameter was 0.7 cm (interquartile range: 0.5-0.8 cm). Recall strategies varied, with only 27.8% of patients undergoing guideline-concordant ultrasound within 3-6 months. Over a median follow-up of 26 months, 42 patients developed PLC (39 HCC and 3 cholangiocarcinoma), yielding an incidence of 25.7 cases (95% CI, 6.2-47.0) per 1000 person-years, with 3.9% and 6.7% developing PLC at 2 and 3 years, respectively. Factors associated with time-to-PLC were baseline alpha-fetoprotein >10 ng/mL (HR: 4.01, 95% CI, 1.85-8.71), platelet count ≤150 (HR: 4.90, 95% CI, 1.95-12.28), and Child-Pugh B cirrhosis (vs. Child-Pugh A: HR: 2.54, 95% CI, 1.27-5.08).ConclusionsRecall patterns for patients with subcentimeter liver lesions on ultrasound varied widely. The low risk of PLC in these patients supports short-interval ultrasound in 3-6 months, although diagnostic CT/MRI may be warranted for high-risk subgroups such as those with elevated alpha-fetoprotein levels.