Long-term Growth Arrest and Regrowth of Human Dermal Fibroblasts after 8-MOP plus UVA Treatment � Implications for Stress-Induced Premature Senescence and Replicative Cellular Senescence

Following psoralen photoactivation (PUVA) human dermal fibroblasts undergo long-term growth arrest as well as morphological and functional changes reminiscent of cellular senescence. In the absence of molecular data what constitutes normal senescence, it has been difficult to decide whether these PUVA-induced changes reflect cellular senescence or rather a mimic thereof. By contrast to replicative senescence, PUVA-induced growth arrest was reversible. Ninety to 120 days post PUVA treatment, cells start to regrow. As cellular senescence has been proposed to serve as a barrier for tumorigenesis, the escape from senescence was studied in regard to immortalization and transformation. Regrowing fibroblasts did not show telomerase activity which is a main way to ensure immortalization. Anchorage-independent growth, a hallmark of transformation, was not detected. In addition, the senescence control genes p53, p16 and p21 did not show obvious mutations. Together with the observation that regrowing fibroblasts underwent replicative senescence, these results indicate that regrowing fibroblasts were neither immortalized nor transformed. PUVA-induced senescence features were reversible. Enlarged cell morphology, expression of senescence-associated (SA) -galactosidase and matrix-metalloprotease-1 were lost when fibroblasts resumed growth. Senescence control genes p53 and p21 were maintained for 1 month, whereas upregulation of p16 was maintained during the whole growth arrest. ROS levels were elevated increasingly after PUVA treatment with a maximum of 20-fold at six weeks post PUVA, which is both due to mitochondria and NADPH oxidase. Scavenging of ROS by the antioxidant N-acetyl cystein (NAC) prevented PUVA-treated fibroblasts from cytoplasmic enlargement but not from SA--galactosidase expression suggesting a role of ROS in the induction of phenotypical but not of functional senescent changes. Interestingly, PUVA-treated fibroblasts cultured in their regrowing state reach the stationary phase at a much lower cumulative population doubling than control fibroblasts. The reduced total life-span was due to oxidative stress induced telomere erosion as scavenging of ROS by NAC rescued cell from telomere erosion and partly restored the life-span. These data support the view that the preceding damage affects a counting mechanism contributing to the overall proliferation potential. The initiation of the growth arrest was studied, and the amount of interstrand cross-links was not correlative. To further study whether damaged cytoplasts or damaged nuclear DNA are responsible for the growth arrest, nuclei and cytoplasts of PUVA-treated fibroblasts were fused with control cytoplasts or nuclei to reconstruct hybrids with either undamaged cytoplasts or undamaged nuclei. Fused cells with PUVA-cytoplasts, although growth arrested, start to regrow earlier post-PUVA at about day 40. Fused cells with PUVA-karyoplasts did not adopt a flattened phenotype and die after 2 weeks. These data indicate that PUVA-induced changes in the cytoplasts contribute to growth arrest, but may not be exclusively, while the contribution of the nuclear damage after PUVA cannot be fully evaluated by these experiments. Collectively, these data suggest that PUVA-induced changes do not fully reflect replicative senescence but rather represent a long-term transient phenocopy. The model reported here is particularly suited to elucidating mechanisms underlying long-term senescence-like growth arrest and related functional changes

A Unified Approximation Framework for Compressing and Accelerating Deep Neural Networks

Deep neural networks (DNNs) have achieved significant success in a variety of real world applications, i.e., image classification. However, tons of parameters in the networks restrict the efficiency of neural networks due to the large model size and the intensive computation. To address this issue, various approximation techniques have been investigated, which seek for a light weighted network with little performance degradation in exchange of smaller model size or faster inference. Both low-rankness and sparsity are appealing properties for the network approximation. In this paper we propose a unified framework to compress the convolutional neural networks (CNNs) by combining these two properties, while taking the nonlinear activation into consideration. Each layer in the network is approximated by the sum of a structured sparse component and a low-rank component, which is formulated as an optimization problem. Then, an extended version of alternating direction method of multipliers (ADMM) with guaranteed convergence is presented to solve the relaxed optimization problem. Experiments are carried out on VGG-16, AlexNet and GoogLeNet with large image classification datasets. The results outperform previous work in terms of accuracy degradation, compression rate and speedup ratio. The proposed method is able to remarkably compress the model (with up to 4.9x reduction of parameters) at a cost of little loss or without loss on accuracy.Comment: 8 pages, 5 figures, 6 table

Sex-Specific Clinical Characteristics and Long-Term Outcomes in Patients With Myocardial Infarction With Non-obstructive Coronary Arteries

Background: Sex differences in clinical profiles and prognosis after acute myocardial infarction have been addressed for decades. However, the sex-based disparities among patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) remain largely unreported. Here, we investigated sex-specific characteristics and long-term outcomes in MINOCA population.Methods: A total of 1,179 MINOCA patients were enrolled, including 867 men and 312 women. The mean follow-up was 41.7 months. The primary endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, non-fatal reinfarction, revascularization, non-fatal stroke, and hospitalization for unstable angina or heart failure. Baseline data and outcomes were compared. Kaplan-Meier curves and Cox regression analyses were used to identify association between sex and prognosis.Results: Female patients with MINOCA had more risk profiles with regard to older age and higher prevalence of hypertension and diabetes compared with men. The evidence-based medical treatment was similar in men and women. The incidence of MACE (men vs. women: 13.8 vs. 15.3%, p = 0.504) did not differ significantly between the sexes. The Kaplan-Meier analysis also indicated that women had a similar incidence of MACE compared to men (log rank p = 0.385). After multivariate adjustment, female sex was not associated with the risk of MACE in overall (adjusted hazard ratio 1.02, 95% confidence interval: 0.72–1.44, p = 0.916) and in subgroups of MINOCA patients.Conclusion: The long-term outcomes were similar for men and women presenting with MINOCA despite older age and more comorbidities in women. Future research should aim to improve in-hospital and post-discharge care for both sexes with MINOCA

Hazardous Gas Emission Monitoring Based on High-Resolution Images

Air pollution presents unprecedentedly severe challenges to humans today. Various measures have been taken to monitor pollution from gas emissions and the changing atmosphere, of which imaging is of crucial importance. By images of target scenes, intuitional judgments and in-depth data are achievable. However, due to the limitations of imaging devices, effective and efficient monitoring work is often hindered by low-resolution target images. To deal with this problem, a superresolution reconstruction method was proposed in this study for high-resolution monitoring images. It was based on the idea of sparse representation. Particularly, multiple dictionary pairs were trained according to the gradient features of samples, and one optimal pair of dictionaries was chosen to reconstruct by judging the weighting of the information in different directions. Furthermore, the K-means singular value decomposition algorithm was used to train the dictionaries and the orthogonal matching pursuit algorithm was employed to calculate the sparse coding coefficients. Finally, the experiment’s results demonstrated its advantages in both visual fidelity and numerical measures

A potential predictor of multi - season droughts in Southwest China: soil moisture and its memory

During the last decade, several high intensity and long duration droughts happened in Southwest China (SWC) and resulted in tremendous socioeconomic losses. Meanwhile, it is well known that soil moisture (SM) plays a key role in land–atmosphere interaction and weather/climate prediction and is a direct drought index. Thus, a general analysis of SM is beneficial to drought research and prediction over this region. Based on the SM data of Global Land Data Assimilation System V2.0, we examined the temporal variations in SM in SWC during 1961–2012. Results show that significant soil drying trend happened in autumn accompanied by an evident abrupt change in 1991. Moreover, SM exhibits a strong and season-dependent persistence. Particularly, the autumn SM anomaly shows the strongest memory that can be sustained to the next spring. Along with the decadal shift of SM, the memory time of autumn SM can extend from 3 months before 1991 to 6 months in recent years. We further used the Standardized Precipitation Evapotranspiration Index (SPEI) at multiple time scales to identify the droughts in different seasons over SWC, and the inter-annual change patterns of autumn SM and SPEIs are generally in agreement with each other, which confirms that SM is suitable for indicating the droughts. Our results suggest that the autumn SM can be a potential predictor of persistent droughts over SWC, especially for those multi-season persistent drought events started in autumn

Frequency tuning behaviour of terahertz quantum cascade lasers revealed by a laser beating scheme

In the terahertz frequency range, the commercialized spectrometers, such as the Fourier transform infrared and time domain spectroscopies, show spectral resolutions between a hundred megahertz and a few gigahertz. Therefore, the high precision frequency tuning ability of terahertz lasers cannot be revealed by these traditional spectroscopic techniques. In this work, we demonstrate a laser beating experiment to investigate the frequency tuning characteristics of terahertz quantum cascade lasers (QCLs) induced by temperature or drive current. Two terahertz QCLs emitting around 4.2 THz with identical active regions and laser dimensions (150 μm wide and 6 mm long) are employed in the beating experiment. One laser is operated as a frequency comb and the other one is driven at a lower current to emit a single frequency. To measure the beating signal, the single mode laser is used as a fast detector (laser self-detection). The laser beating scheme allows the high precision measurement of the frequency tuning of the single mode terahertz QCL. The experimental results show that in the investigated temperature and current ranges, the frequency tuning coefficients of the terahertz QCL are 6.1 MHz/0.1 K (temperature tuning) and 2.7 MHz/mA (current tuning) that cannot be revealed by a traditional terahertz spectrometer. The laser beating technique shows potential abilities in high precision linewidth measurements of narrow absorption lines and multi-channel terahertz communications

Prediction of hip joint load and translation using musculoskeletal modelling with force-dependent kinematics and experimental validation

Musculoskeletal (MSK) lower limb models are widely used to predict the resultant contact force in the hip joint as a non-invasive alternative to instrumented implants. Previous MSK models based on rigid body assumptions treated the hip joint as an ideal sphere with only three rotational degrees of freedom (DOFs). An MSK model that considered force-dependent kinematics (FDK) with three additional translational DOFs was developed and validated in the present study by comparing it with a previous experimental measurement. A 32-mm femoral head against a polyethylene cup was considered in the MSK model for calculating the contact forces. The changes in the main modelling 28 parameters were found to have little influence on the hip joint forces (RDPV<10 BW%, mean trial deviation<20 BW%). The centre of the hip joint translation was more sensitive to the changes in the main modelling parameters, especially muscle recruitment type (RDPV<20%, mean trial deviation<0.02 mm). The predicted hip contact forces (HCFs) showed consistent profiles, compared with the experimental measurements, except in the lateral-medial direction. The ratio-average analysis, based on the Bland and Altman’s plots, showed better limits of agreement (LOA) in climbing stairs (mean LOA: -2.0 to 6.3 in walking, mean LOA: -0.5 to 3.1 in climbing stairs). Better agreement of the predicted HCFs was also found during the stance phase. The FDK approach underestimated the maximum hip contact force by a mean value of 6.68 ±1.75% BW compared with the experimental measurements. The predicted maximum translations of the hip joint centres were 0.125 ± 0.03 mm in level walking and 0.123 ± 0.005 mm in climbing stairs

Effects of mulberry twig alkaloids(Sangzhi alkaloids) and metformin on blood glucose fluctuations in combination with premixed insulin-treated patients with type 2 diabetes

IntroductionWe aimed to evaluated the effect of premixed insulin (Ins), premixed insulin combined with metformin (Ins+Met) or mulberry twig alkaloids(Ins+SZ-A) on blood glucose fluctuations in patients with type 2 diabetes (T2DM) using continuous glucose monitors (CGM).MethodsThirty patients with T2DM and poor blood glucose control using drugs were evaluated for eligibility during the screening period. Subsequently, their original hypoglycemic drugs were discontinued during the lead-in period, and after receiving Ins intensive treatment for 2 weeks, they were randomly assigned to receive either Ins, Ins+Met, or Ins+SZ-A treatment for the following 12 weeks. The main efficacy endpoint comprised changes in their CGM indicators changes (mean blood glucose level [MBG], standard deviation of blood glucose [SDBG], mean amplitude of glycemic excursions [MAGE], postprandial glucose excursions [PPGE], the largest amplitude of glycemic excursions [LAGE], mean of daily difference [MODD], time in range between 3.9–10.0 mmol/L [TIR] and area under the curve for each meal [AUCpp]) during the screening, lead-in, and after 12-week treatment period. Changes in glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), 1-h postprandial blood glucose (1h-PBG), 2-h postprandial blood glucose (2h-PBG), fasting blood lipids and postprandial blood lipids were also measured at baseline and after 12 weeks of treatmentResultsThe CGM indicators of the three groups during the lead-in period all showed significant improvements compared to the screening period (P&lt;0.05). Compared with those in the lead-in period, all of the CGM indicators improved in the the Ins+Met and Ins+SZ-A groups after 12 weeks of treatment (P&lt;0.05), except for MODD. After 12-week treatment, compared with the Ins group, Ins+Met and Ins+SZ-A groups showed improved MBG, SDBG, TIR, breakfast AUCpp,lunch AUCpp, HbA1c, FBG, 1h-PBG, fasting blood lipid and postprandial blood lipid indicators (P&lt;0.05). Further, the LAGE, PPGE, MAGE, dinner AUCpp and 2h-PBG levels of the Ins+SZ-A group were significantly lower than those of the Ins+Met and Ins groups (P&lt;0.05).ConclusionOur findings highlight the efficacy of combination therapy (Ins+SZ-A or Ins+Met) in improving blood glucose fluctuations, as well as blood glucose and lipid levels. Ins+SZ-A reduces postprandial blood glucose fluctuations more than Ins+Met and Ins groups.Trial registration numberISRCTN20835488