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Can Tu,1,2 Ming Niu,2 Ai-Wu Wei,3 Jin-Fa Tang,3 Le Zhang,2 Jing Jing,2 Xiao-He Xiao,2 Jia-Bo Wang2,4 1Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China; 3The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450000, People’s Republic of China; 4School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, People’s Republic of ChinaCorrespondence: Jia-Bo WangSchool of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, People’s Republic of ChinaEmail pharm_sci@126.comXiao-He XiaoChina Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of ChinaEmail pharmacy302xxh@126.comBackground: Drug-induced liver injury is a common adverse effect in clinical practice, with severe cases resulting in liver failure and even death. Identification and prediction of individuals susceptible to idiosyncratic DILI continues to remain a challenge.Methods: In this study, we report that cytokines in human serum can be used to identify and predict individuals susceptible to Polygonum multiflorum-induced DILI (PM-DILI) in retrospective and prospective cohort studies.Findings: In the retrospective pilot study, we compared serum cytokine expression profiles of the PM-DILI group (n=10) and the PM-Tolerant group (n=12) and found 10 cytokines with significant differences. In the replication cohort study, differences in the 10 cytokines between PM-DILI (n =11) and PM-Tolerant (n=13) groups were verified. Among them, 6 cytokines showed no significant differences at two time points, including liver injury and recovery stage of PM-DILI, suggesting that these 6 cytokines have no correlation with PM-DILI, however, they may be related to susceptibility. Furthermore, all the retrospective cohorts were combined, and a PM-DILI susceptibility prediction model was built by screening the 6 cytokines. The combination of (TNF-α and CCL-2) or VEGF showed the highest sensitivity and specificity. Finally, the efficacy of the above 3 cytokine combination models in predicting PM-DILI-susceptible individuals was verified before PM exposure in another independent prospective cohort (n=24), with sensitivity and specificity of 66.7% and 83.3%, respectively.Conclusion: This proof-of-concept study demonstrates that the serum cytokine combination reflecting dysimmunity could be used as a new method to predict PM-DILI, thus providing a new perspective for improving the clinical management of IDILI.Keywords: drug-induced liver injury, Polygonum multiflorum, cytokine, prediction, susceptible individual

Yuqing Mao,1 Fujun Yu,1 Jianbo Wang,2 Chuanyong Guo,3 Xiaoming Fan1 1Department of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, Shanghai, 2Department of Gastroenterology and Hepatology, The Central Hospital of Lishui City, Wenzhou Medical University, Zhejiang, 3Department of Gastroenterology and Hepatology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, People's Republic of China Abstract: Nonalcoholic fatty liver disease (NAFLD) has gained importance in recent decades due to drastic changes in diet, especially in Western countries. NAFLD occurs as a spectrum from simple hepatic steatosis, steatohepatitis to cirrhosis, and even hepatocellular carcinoma. Although the molecular mechanisms underlying the development of NAFLD have been intensively investigated, many issues remain to be resolved. Autophagy is a cell survival mechanism for disposing of excess or defective organelles, and has become a hot spot for research. Recent studies have revealed that autophagy is linked to the development of NAFLD and regulation of autophagy has therapeutic potential. Autophagy reduces intracellular lipid droplets by enclosing them and fusing with lysosomes for degradation. Furthermore, autophagy is involved in attenuating inflammation and liver injury. However, autophagy is regarded as a double-edged sword, as it may also affect adipogenesis and adipocyte differentiation. Moreover, it is unclear as to whether autophagy protects the body from injury or causes diseases and even death, and the association between autophagy and NAFLD remains controversial. This review is intended to discuss, comment, and outline the progress made in this field and establish the possible molecular mechanism involved. Keywords: nonalcoholic fatty liver disease, autophagy, steatosis, steatohepatitis, fibrosis, carcinogenesis

Yuqing Mao,1 Jianbo Wang,2 Fujun Yu,1 Jian Cheng,1 Huanqing Li,1 Chuanyong Guo,3 Xiaoming Fan11Department of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, Shanghai, 2Department of Gastroenterology and Hepatology, The Central Hospital of Lishui City, Wenzhou Medical University, Zhejiang, 3Department of Gastroenterology and Hepatology, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, People’s Republic of ChinaBackground and aims: Ghrelin is a 28-amino-acid gut hormone that was first discovered as a potent growth hormone secretagogue. Recently, it has been shown to exert a strong anti-inflammatory effect. The purpose of the study reported here was to explore the effect and mechanism of ghrelin on concanavalin (Con) A-induced acute hepatitis.Methods: Balb/C mice were divided into four groups: normal control (NC) (mice injected with vehicle [saline]); Con A (25 mg/kg); Con A + 10 µg/kg ghrelin; and Con A + 50 µg/kg ghrelin (1 hour before Con A injection). Pro-inflammatory cytokine levels were detected. Protein levels of phosphoinositide 3-kinase (PI3K); phosphorylated Akt (p-Akt); caspase 3, 8, and 9; and microtubule-associated protein 1 light chain 3 (LC3) were also detected. Perifosine (25 mM) (an Akt inhibitor) was used to investigate whether the protective effect of ghrelin was interrupted by an Akt inhibitor. Protein levels of p-AKT; Bcl-2; Bax; and caspase 3, 8, and 9 were also detected.Results: Aspartate aminotransferase, alanine aminotransferase, and pathological damage were significantly ameliorated by ghrelin pretreatment in Con A-induced hepatitis. Inflammatory cytokines were significantly reduced by ghrelin pretreatment. Bcl-2; Bax; and caspase 3, 8, and 9 expression were also clearly affected by ghrelin pretreatment, compared with the Con A-treated group. However, the Akt kinase inhibitor reversed the decrease of Bax and caspase 3, 8, 9, and reduced the protein level of p-Akt and Bcl-2. Ghrelin activated the PI3K/Akt/Bcl-2 pathway and inhibited activation of autophagy.Conclusion: Our results demonstrate that ghrelin attenuates Con A-induced acute immune hepatitis by activating the PI3K/Akt pathway and inhibiting the process of autophagy, which might be related to inhibition of inflammatory cytokine release, and prevention of hepatocyte apoptosis. These effects could be interrupted by an Akt kinase inhibitor.Keywords: PI3K/Akt pathway, autophagy, inflammation, apoptosis

Lili Qin,1,* Wenrui Wang,2,* Songhui You,1 Jingmei Dong,1 Yunhe Zhou,1 Jibing Wang1 1Department of Physical Education, 2School of Life Science and Technology, Tongji University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Folic acid antioxidants were successfully intercalated into layered double hydroxides (LDH) nanoparticles according to a previous method with minor modification. The resultant folic acid-LDH constructs were then characterized by X-ray powder diffraction and transmission electron microscopy. The in vitro antioxidant activities, cytotoxicity effect, and in vivo anti­fatigue were examined by a series of assays. The results showed that folic acid-LDH antioxidant system can scavenge 1,1-diphenyl-2-picrylhydrazyl and hydroxyl free radicals and chelate pro-oxidative Cu2+. The in vitro cytotoxicity assays indicated that folic acid-LDH antioxidant system had no significant cytotoxic effect or obvious toxicity to normal cells. It also prolonged the forced swimming time of the mice by 32% and 51% compared to folic acid and control groups, respectively. It had an obvious effect on decreasing the blood urea nitrogen and blood lactic acid, while increasing muscle and hepatic glycogen levels. Therefore, folic acid-LDH might be used as a novel antioxidant and antifatigue nutritional supplement. Keywords: antioxidant supplementation, free radicals, biomaterials, drug delivery

Zhenyu Zhang,1 Jianbing Wang,1 Mingjuan Jin,1 Mei Li,1 Litao Zhou,2 Fangyuan Jing,1 Kun Chen1 1Department of Epidemiology and Health Statistics, School of Public Health, Zhejiang University, Zhejiang, People’s Republic of China; 2Quality Control Department, Zhejiang Hospital, Zhejiang, People’s Republic of China Background: The People’s Republic of China’s population is aging rapidly, partly because of the impact of the one-child policy and improvements in the health care system. Caring for bedridden seniors can be a challenge for many families in the People’s Republic of China.Objective: To identify the inequality of income among different age groups and social statuses, and evaluate the medical burden and health insurance compensation in the People’s Republic of China.Methods: We measured income inequality and insurance compensation levels among bedridden patients in Zhejiang province, People’s Republic of China. Factor analysis and Gini coefficients were used to evaluate degree of income inequality and insurance compensation level.Results: We found distinct regional disparities in Zhejiang province, including the aspects of income, expenses, and time. Gini coefficients of older adults with long-term care needs in urban and rural areas were 0.335 and 0.602, respectively. In all age groups, Gini coefficients increased after adjustment for medical expenditures, and the inequality persisted after insurance reimbursement was taken into consideration.Conclusion: A significant income disparity between rural and urban areas was observed. Inequality increased with age, and medical expenditure is a huge burden for older people with long-term care needs. Health insurance does not play an important role in reducing inequalities among patients who need long-term care services. Keywords: Gini coefficient, bedridden, long-term care, insurance

Abstract With a bottom-up assemble technology, heterogeneous magnetic nanobrushes, consisting of Co nanowire arrays and ferromagnetic Fe70Co30 nanofilm, have been fabricated using an anodic aluminum oxide template method combining with sputtering technology. Magnetic measurement suggests that the magnetic anisotropy of nanobrush depends on the thickness of Fe70Co30 layer, and its total anisotropy originates from the competition between the shape anisotropy of nanowire arrays and nanofilm. Micromagnetic simulation result indicates that the switching field of nanobrush is 1900 Oe, while that of nanowire array is 2700 Oe. These suggest that the nanobrush film can promote the magnetization reversal processes of nanowire arrays in nanobrush.

Abstract The field emission properties of SnO2nanowires fabricated by chemical vapor deposition with metallic catalyst-assistance were investigated. For the as-fabricated SnO2nanowires, the turn-on and threshold field were 4.03 and 5.4 V/μm, respectively. Considerable enhancement of field emission of SnO2nanowires was obtained by a post-annealing process in oxygen at high temperature. When the SnO2nanowires were post-annealed at 1,000 °C in oxygen, the turn-on and threshold field were decreased to 3.77 and 4.4 V/μm, respectively, and the current density was increased to 6.58 from 0.3 mA/cm2at the same applied electric field of 5.0 V/μm.

We have constructed a new time-scale, TT(IPTA16), based on observations of radio pulsars presented in the first data release from the International Pulsar Timing Array (IPTA). We used two analysis techniques with independent estimates of the noise models for the pulsar observations and different algorithms for obtaining the pulsar time-scale. The two analyses agree within the estimated uncertainties and both agree with TT(BIPM17), a post-corrected time-scale produced by the Bureau International des Poids et Mesures (BIPM). We show that both methods could detect significant errors in TT(BIPM17) if they were present. We estimate the stability of the atomic clocks from which TT(BIPM17) is derived using observations of four rubidium fountain clocks at the US Naval Observatory. Comparing the power spectrum of TT(IPTA16) with that of these fountain clocks suggests that pulsar-based time-scales are unlikely to contribute to the stability of the best time-scales over the next decade, but they will remain a valuable independent check on atomic time-scales. We also find that the stability of the pulsar-based time-scale is likely to be limited by our knowledge of solar-system dynamics, and that errors in TT(BIPM17) will not be a limiting factor for the primary goal of the IPTA, which is to search for the signatures of nano-Hertz gravitational waves.

Catheter-based intra-arterial drug therapies have proven effective for a range of oncologic, neurologic, and cardiovascular applications. However, these procedures are limited by their invasiveness and relatively broad drug spatial distribution. The ideal technique for local pharmacotherapy would be noninvasive and would flexibly deliver a given drug to any region of the body with high spatial and temporal precision. Combining polymeric perfluorocarbon nanoemulsions with existent clinical focused ultrasound systems could in principle meet these needs, but it has not been clear whether these nanoparticles could provide the necessary drug loading, stability, and generalizability across a range of drugs, beyond a few niche applications. Here, we develop polymeric perfluorocarbon nanoemulsions into a generalized platform for ultrasound-targeted delivery of hydrophobic drugs with high potential for clinical translation. We demonstrate that a wide variety of drugs may be effectively uncaged with ultrasound using these nanoparticles, with drug loading increasing with hydrophobicity. We also set the stage for clinical translation by delineating production protocols that are scalable and yield sterile, stable, and optimized ultrasound-activated drug-loaded nanoemulsions. Finally, we exhibit a new potential application of these nanoemulsions for local control of vascular tone. This work establishes the power of polymeric perfluorocarbon nanoemulsions as a clinically-translatable platform for efficacious, noninvasive, and localized ultrasonic drug uncaging for myriad targets in the brain and body.

We analyse the stochastic properties of the 49 pulsars that comprise the first International Pulsar Timing Array (IPTA) data release. We use Bayesian methodology, performing model selection to determine the optimal description of the stochastic signals present in each pulsar. In addition to spin-noise and dispersion-measure (DM) variations, these models can include timing noise unique to a single observing system, or frequency band. We show the improved radio-frequency coverage and presence of overlapping data from different observing systems in the IPTA data set enables us to separate both system and band-dependent effects with much greater efficacy than in the individual pulsar timing array (PTA) data sets. For example, we show that PSR J1643-1224 has, in addition to DM variations, significant band-dependent noise that is coherent between PTAs which we interpret as coming from time-variable scattering or refraction in the ionized interstellar medium. Failing to model these different contributions appropriately can dramatically alter the astrophysical interpretation of the stochastic signals observed in the residuals. In some cases, the spectral exponent of the spin-noise signal can vary from 1.6 to 4 depending upon the model, which has direct implications for the long-term sensitivity of the pulsar to a stochastic gravitational-wave (GW) background. By using a more appropriate model, however, we can greatly improve a pulsar's sensitivity to GWs. For example, including system and band-dependent signals in the PSR J0437-4715 data set improves the upper limit on a fiducial GW background by ~60 per cent compared to a model that includes DM variations and spin-noise only.

Extreme scattering events (ESEs) in the interstellar medium (ISM) were first observed in regular flux measurements of compact extragalactic sources. They are characterized by a flux variation over a period of weeks, suggesting the passage of a "diverging plasma lens" across the line of sight (LOS). Modeling the refraction of such a lens indicates that the structure size must be of the order of AU and the electron density of the order of 10s of cm-3. Similar structures have been observed in measurements of pulsar intensity scintillation and group delay. Here we report observations of two ESEs, showing increases in both intensity scintillation and dispersion made with the Parkes Pulsar Timing Array. These allow us to make more complete models of the ESE, including an estimate of the "outer-scale" of the turbulence in the plasma lens. These observations clearly show that the ESE structure is fully turbulent on an AU scale. They provide some support for the idea that the structures are extended along the LOS, such as would be the case for a scattering shell. The dispersion measurements also show a variety of AU scale structures that would not be called ESEs, yet involve electron density variations typical of ESEs and likely have the same origin.

Background: Depressive symptoms can lower adherence and change in dietary studies. Behavioral activation may reduce these effects. Purpose: This study aims to assess relationships among depressive symptoms on adherence and dietary change in the Women’s Healthy Eating and Living (WHEL) Study Methods: Secondary analyses from the WHEL Study, which achieved major dietary change in breast cancer survivors (N = 2817), were conducted. Logistic regressions were undertaken of baseline depressive symptoms (six-item Center for Epidemiologic Studies Depression Scale (CES-D)) with (1) completion of 1- and 4-year study assessments and (2) validated change in dietary behavior in the intervention group. Results: In the comparison group (vs. intervention), depressive symptoms lowered completion of dietary recalls and clinic visits [4 years: odds ratio (OR) = 2.0; 95 % confidence interval (CI) = 1.4–3.0]. The behaviorally oriented intervention achieved major change in those furthest from study targets, although changes were lower in those with depressive symptoms: fruit/vegetable (+37.2 %), fiber (+49.0 %), and fat (−22.4 %). Conclusions: Behavioral activation in dietary change interventions can overcome the impact of depressive symptoms.

We present results of an all-sky search in the Parkes Pulsar Timing Array (PPTA) Data Release 1 data set for continuous gravitational waves (GWs) in the frequency range from 5 × 10-9 to 2 × 10-7 Hz. Such signals could be produced by individual supermassive binary black hole systems in the early stage of coalescence.We phase up the pulsar timing array data set to form, for each position on the sky, two data streams that correspond to the twoGWpolarizations and then carry out an optimal search for GW signals on these data streams. Since no statistically significant GWs were detected, we place upper limits on the intrinsic GW strain amplitude h0 for a range of GW frequencies. For example, at 10-8 Hz our analysis has excluded with 95 per cent confidence the presence of signals with h0 ≥ 1.7 × 10-14. Our new limits are about a factor of 4 more stringent than those of Yardley et al. based on an earlier PPTA data set and a factor of 2 better than those reported in the recent Arzoumanian et al. paper.We also present PPTA directional sensitivity curves and find that for the most sensitive region on the sky, the current data set is sensitive to GWs from circular supermassive binary black holes with chirp masses of 109M⊙ out to a luminosity distance of about 100 Mpc. Finally, we set an upper limit of 4 × 10-3 Mpc-3 Gyr-1 at 95 per cent confidence on the coalescence rate of nearby (z ≲ 0.1) supermassive binary black holes in circular orbits with chirp masses of 1010M⊙.

High-sensitivity radio-frequency observations of millisecond pulsars usually show stochastic, broad-band, pulse-shape variations intrinsic to the pulsar emission process. These variations induce jitter noise in pulsar timing observations; understanding the properties of this noise is of particular importance for the effort to detect gravitational waves with pulsar timing arrays. We assess the short-term profile and timing stability of 22 millisecond pulsars that are part of the Parkes Pulsar Timing Array sample by examining intraobservation arrival time variability and single-pulse phenomenology. In 7 of the 22 pulsars, in the band centred at approximately 1400 MHz, we find that the brightest observations are limited by intrinsic jitter. We find consistent results, either detections or upper limits, for jitter noise in other frequency bands. PSR J1909-3744 shows the lowest levels of jitter noise, which we estimate to contribute ~10 ns root mean square error to the arrival times for hour-duration observations. Larger levels of jitter noise are found in pulsars with wider pulses and distributions of pulse intensities. The jitter noise in PSR J0437-4715 decorrelates over a bandwidth of ∼2 GHz. We show that the uncertainties associated with timing pulsar models can be improved by including physically motivated jitter uncertainties. Pulse-shape variations will limit the timing precision at future, more sensitive, telescopes; it is imperative to account for this noise when designing instrumentation and timing campaigns for these facilities. © 2014 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society.

Purpose: To investigate the role of Ca²(+) in lipofuscin formation in human retinal pigment epithelial (RPE) cells that phagocytize bovine photoreceptor outer segments (POSs).Methods: Cultured human RPE cells fed with 2 × 10⁷per l bovine POS were treated with flunarizine, an antagonist of Ca²(+) channel, or/and centrophenoxine, a lipofuscin scavenger. The Ca²(+) changes and lipofuscin formation were measured with fluoresence dye Fluo-3/AM ester, laser scanning confocal microscopy (LSCM) and flow cytometry (FCM). The activity of RPE cells was measured by methyl thiazolyl tetrazolium (MTT) assay and argyrophilic nucleolar organizer regions (AgNORs) assay.Results: The Ca²(+) fluorescence intensity (CFI) of RPE cells fed with POS was significantly increased compared with the controls (165.36 ± 29.92 U). It reached a peak with 777.33 ± 63.86 U (P<0.01) at 12 h, and then decreased but still maintained a high level of 316.90 ± 36.07 U (P<0.01) for 4 days. Flunarizine and centrophenoxine significantly decreased the Ca²(+) overload to 227.18 ± 14.00 U at 12 h and 211.06 ± 20.45 U at 4 days. FCM confirmed these changes. The drugs also showed an inhibitory effect on the lipofuscin formation. The proliferation rate of the cells fed with POS increased significantly. Both drugs had inhibitory effects on the activity of the cultured cells. This tendency was confirmed by AgNORs assay.Conclusions: The Ca²(+) inflow initiated lipofuscin accumulation in RPE cells fed with POS. Flunarizine and centrophenoxine can decrease Ca²(+) overload and lipofuscin formation in RPE cells, accompanied by maintaining cellular vitality. [ABSTRACT FROM AUTHOR]

Objective: We designed a carotid siphon (CS) aneurysm model in dogs to test a new stent graft (the Willis covered stent) and compared tissue reaction over 12-month follow-up versus a comparison group with stents implanted in straight vessels.Methods: Twenty-four saccular sidewall aneurysms (group A) and 12 CS aneurysms (group B) were created surgically. A Willis stent graft was implanted in each aneurysm. Angiography was performed immediately and at 1-, 3-, 6- and 12-month post-implantation to investigate aneurysm isolation, endoleak, stent angulation, parent artery (PA) patency and restenosis. Light and scanning electron microscopy were used to identify aneurysmal sac thrombi, intima hyperplasia and endothelial progress.Results: Immediate angiography demonstrated mild endoleak in two aneurysms and three stent angulations in group B. Follow-up at 12 months revealed resolved endoleaks, occlusion in one PA and mild stenosis in three in group B. In group A, occlusion occurred in one PA and mild stenosis in two. Light microscopy revealed new intima, and all aneurysm sacs were filled with thrombi. In group B, endothelial progress was complete at 12 months, and closely correlated with haemodynamic changes.Conclusions: Application of a Willis stent graft is a feasible method of treating CS aneurysms, and it exhibits a prolonged endothelial progress compared with that in straight vessels. [ABSTRACT FROM AUTHOR]