bluuebunny/crossref_metadata_2025 huggingface dataset:
TGF-β1 modifies histone acetylation and acetyl-coenzyme A metabolism in renal myofibroblasts
Authors: Smith Edward R. , Wigg Belinda , Holt Stephen G. , Hewitson Timothy D.
Published: January 2019

Histone acetylation is an important modulator of gene expression in fibrosis. This study examined the effect of the pre-eminent fibrogenic cytokine transforming growth factor-β1 (TGF-β1) on histone 3 (H3) acetylation and its regulatory kinetics in renal myofibroblasts. Fibroblasts propagated from rat kidneys after ureteric obstruction were treated with recombinant TGF-β1 or vehicle for 48 h. TGF-β1-induced myofibroblast activation was accompanied by a net decrease in total H3 acetylation, although changes in individual marks were variable. This was paralleled by a generalized reduction in histone acetyltransferases (HAT) and divergent changes in histone deacetylase (HDAC) enzymes at both transcript and protein levels. Globally, this was manifest in a reduction in total HAT activity and increase in HDAC activity. TGF-β1 induced a shift in cellular metabolism from oxidative respiration to aerobic glycolysis, resulting in reduced acetyl-CoA. The reduction in total H3 acetylation could be rescued by providing exogenous citrate or alternative sources of acetyl-CoA without ameliorating changes in HAT/HDAC activity. In conclusion, TGF-β1 produces a metabolic reprogramming in renal fibroblasts, with less H3 acetylation through reduced acetylation, increased deacetylation, and changes in carbon availability. Our results suggest that acetyl-CoA availability predominates over HAT and HDAC activity as a key determinant of H3 acetylation in response to TGF-β1.
Operant conditioning of the motor-evoked potential and locomotion in people with and without chronic incomplete spinal cord injury
Authors: Thompson Aiko K. , Fiorenza Gina , Smyth Lindsay , Favale Briana , Brangaccio Jodi , Sniffen Janice
Published: January 2019

Foot drop is very common among people with chronic incomplete spinal cord injury (SCI) and likely stems from SCI that disturbs the corticospinal activation of the ankle dorsiflexor tibialis anterior (TA). Thus, if one can recover or increase the corticospinal excitability reduced by SCI, motor function recovery may be facilitated. Here, we hypothesized that in people suffering from weak dorsiflexion due to chronic incomplete SCI, increasing the TA motor-evoked potential (MEP) through operant up-conditioning can improve dorsiflexion during locomotion, while in people without any injuries, it would have little impact on already normal locomotion. Before and after 24 MEP conditioning or control sessions, locomotor electromyography (EMG) and kinematics were measured. This study reports the results of these locomotor assessments. In participants without SCI, locomotor EMG activity, soleus Hoffmann reflex modulation, and joint kinematics did not change, indicating that MEP up-conditioning or repeated single-pulse transcranial magnetic stimulation (i.e., control protocol) does not influence normal locomotion. In participants with SCI, MEP up-conditioning increased TA activity during the swing-to-swing stance transition phases and ankle joint motion during locomotion in the conditioned leg and increased walking speed consistently. In addition, the swing-phase TA activity and ankle joint motion also improved in the contralateral leg. The results are consistent with our hypothesis. Together with the previous operant conditioning studies in humans and rats, the present study suggests that operant conditioning can be a useful therapeutic tool for enhancing motor function recovery in people with SCI and other central nervous system disorders.

NEW & NOTEWORTHY This study examined the functional impact of operant conditioning of motor-evoked potential (MEP) to transcranial magnetic stimulation that aimed to increase corticospinal excitability for the ankle dorsiflexor tibialis anterior (TA). In people with chronic incomplete spinal cord injury (SCI), MEP up-conditioning increased TA activity and improved dorsiflexion during locomotion, while in people without injuries, it had little impact on already normal locomotion. MEP conditioning may potentially be used to enhance motor function recovery after SCI.
Anterior cingulate cortex encoding of effortful behavior
Authors: Porter Blake S. , Hillman Kristin L. , Bilkey David K.
Published: January 2019

An animal’s ability to assess the value of their behaviors to minimize energy use while maximizing goal achievement is critical to its survival. The anterior cingulate cortex (ACC) has been previously shown to play a critical role in this behavioral optimization process, especially when animals are faced with effortful behaviors. In the present study, we designed a novel task to investigate the role of the ACC in evaluating behaviors that varied in effort but all resulted in the same outcome. We recorded single unit activity from the ACC as rats ran back and forth in a shuttle box that could be tilted to different tilt angles (0, 15, and 25°) to manipulate effort. Overall, a majority of ACC neurons showed selective firing to specific effort conditions. During effort expenditure, ACC units showed a consistent firing rate bias toward the downhill route compared with the more difficult uphill route, regardless of the tilt angle of the apparatus. Once rats completed a run and received their fixed reward, ACC units also showed a clear firing rate preference for the single condition with the highest relative value (25° downhill). To assess effort preferences, we used a choice version of our task and confirmed that rats prefer downhill routes to uphill routes when given the choice. Overall, these results help to elucidate the functional role of the ACC in monitoring and evaluating effortful behaviors that may then bias decision-making toward behaviors with the highest utility.

NEW & NOTEWORTHY We developed a novel effort paradigm to investigate how the anterior cingulate cortex (ACC) responds to behaviors with varied degrees of physical effort and how changes in effort influence the ACC’s evaluation of behavioral outcomes. Our results provide evidence for a wider role of the ACC in its ability to motivate effortful behaviors and evaluate the outcome of multiple behaviors within an environment.
Predictors of Initiating Hormone Replacement Therapy in Postmenopausal Women: A Cross-Sectional Study
Authors: Çilgin Hasan
Published: January 2019

Objectives. Some of the social factors were related to hormone replacement therapy. The purpose of this study is to determine hormone replacement therapy (HRT) rates and to illustrate social factors affecting hormone replacement therapy in postmenopausal women. Material and Methods. This study comprised a total of 1052 postmenopausal women, 926 of whom were reported menopausal symptoms and sought for the treatment. 432 of these 926 participants had treated their symptoms by receiving HRT. The data was collected with a data collection form prepared by the researcher by using face-to-face interview technique. In these analyses, chi-square and Backward Logistic regression analyses were used. Results. The multivariate analyses indicated that the decision to seek treatment was influenced by a multitude of factors. These factors included location of hormone replacement therapy (OR: 12.32 [3.21-44.46] in university hospital and OR: 5.42 [2.43–13.26] in private hospital), information received about HRT (OR: 7.25 [2.14,-30.80]), physicians’ counselling and involvement (OR: 5.24 [2.82-9.86]), knowledge of complications associated with HRT (OR: 6.21 [3.28-16.62]), and employment status (OR: 3.42 [1.86-5.58]). The current study identifies these factors affecting the HRT process in postmenopausal women. Conclusion. This study suggests that although the results do not demonstrate an exhaustive list of factors affecting the HRT process, they nonetheless provide evidence that the location participants applied for, physicians’ counselling and involvement, participant employment status, and knowledge surrounding HRT may affect a woman’s intent to receive HRT. Therefore, these results indicate that health professional influence and HRT awareness are important for HRT use. Suggestions for health care include informing women of the advantages and disadvantages of HRT to encourage popularity.
Angiopoietin-1 Promotes the Integrity of Neovascularization in the Subcutaneous Matrigel of Type 1 Diabetic Rats
Authors: LI ShaoBin , Zou HeQin , Gong MinMin , Chen YuQin , Yan XiaoYong , Yu LiMei , Yang YiBin
Published: January 2019

Objective. This study aimed to investigate the effects of Ang-1 on neovascularization of diabetic organs by subcutaneous Matrigel angiogenesis model, established in type 1 diabetic rats. Methods. Ang-1 adenoviral vector was constructed. The rat model was established by STZ and divided into four group. The Matrigel was inserted subcutaneously into the abdominal cavity of rats at 8 weeks, the treatment group was injected with Ang-1 adenovirus vector via tail vein, and the rats were sacrificed at 10 weeks. Neovascularization of Matrigel was observed with transmission electron microscopy. The marker of vascular endothelial cell and pericyte were detected by immunofluorescence. Immunohistochemical detection of the neovascular endothelial junction protein was performed. RT-PCR was used to determine protein expression of neovascular in Matrigel. Results. Vascular cavity-like structure could be seen in subcutaneous Matrigel of diabetic rats, and the cavity was filled with a lot of red blood cells. Transmission electron microscopy showed that neovascular endothelial structure of the Matrigel was incomplete, while the Ang-1 treatment group had more vascular cavity-like structures, intact vascular endothelial structure, and reduced inflammatory cell infiltration in Matrigel. Additionally, the integrity of vascularization improved, and the marker of pericyte and the cell tight junctions protein was upregulated in Ang-1 treatment group. Conclusion. Hyperglycemia could induce pathological angiogenesis in subcutaneous Matrigel of diabetic rats, and Ang-1 could upregulate the expression of intercellular junction protein in subcutaneous Matrigel of diabetic rats and promote the integrity of neovascularization in the subcutaneous Matrigel of diabetic rats.
Acetaldehyde Induces Neurotoxicity In Vitro via Oxidative Stress- and Ca2+ Imbalance-Mediated Endoplasmic Reticulum Stress
Authors: Cui Jiahui , Liu Yang , Chang Xing , Gou Wenfeng , Zhou Xuejiao , Liu Zi , Li Zengqiang , Wu Yingliang , Zuo Daiying
Published: January 2019

Excessive drinking can damage brain tissue and cause cognitive dysfunction. Studies have found that the early stage of neurodegenerative disease is closely related to heavy drinking. Acetaldehyde (ADE) is the main toxic metabolite of alcohol. However, the exact mechanisms of ADE-induced neurotoxicity are not fully clear. In this article, we studied the cytotoxic effect of ADE in HT22 cells and primary cultured cortical neuronal cells. We found that ADE exhibited cytotoxicities against HT22 cells and primary cultured cortical neuronal cells in dose-dependent manners. Furthermore, ADE induced apoptosis of HT22 cells by upregulating the expression of caspase family proapoptotic proteins. Moreover, ADE treatment could significantly increase the intracellular Ca2+ and reactive oxygen species (ROS) levels and activate endoplasmic reticulum stress (ERS) in HT22 cells. ADE upregulated ERS-related CHOP expression dose-dependently in primary cultured cortical neuronal cells. In addition, inhibition of ROS with antioxidant N-acetyl-L-cysteine (NAC) reduced the accumulation of ROS and reversed ADE-induced increase of ERS-related protein and apoptosis-related protein levels. Mitigation of ERS with ERS inhibitor 4-PBA obviously suppressed ADE-induced apoptosis and the expression of ERS-related proteins. Therefore, ADE induces neurotoxicity of HT22 cells via oxidative stress- and Ca2+ imbalance-mediated ERS.
A Water-Based Synthesis of Hybrid Silica/Hyperbranched Poly(ethylene imine) Nanopowder for Heavy Metal Sorption from Aqueous Solutions
Authors: Kitsou Ioanna , Tsetsekou Athena
Published: January 2019

A novel hybrid, water-based, sol-gel method was developed for the synthesis of functionalized silica with advanced adsorptive capacities towards heavy metal ions. The study employs the hyperbranched poly(ethylene imine) (HBPEI) as a reactive template for the synthesis of silica. The reaction was followed by FTIR, whereas the material was evaluated in terms of its microstructure and adsorptive properties. The results revealed a very potent adsorbent that can remove heavy metal ions (namely, Pb, Cu, and Zn) from water in a fast and efficient way. Greater selectivity was observed for lead, whereas the maximum adsorption capacities calculated from the Langmuir model were 833.3, 502.5, and 193.4 mg/g for lead, copper, and zinc, respectively.
A Two‐Stage Stochastic Model for Maintenance and Rehabilitation Planning of Pavements
Authors: Ameri Mahmoud , Jarrahi Armin , Haddadi Farshad , Mirabimoghaddam Mohammad Hasan
Published: January 2019

Pavement maintenance and rehabilitation (M&R) plan for maintaining the pavement quality in an acceptable level has direct influence on the required budget. Deterministic budgeting is an unrealistic assumption, so, in this study, a two‐stage stochastic model using integer programming is developed to address uncertainty in budgeting. Another aim of this study is to develop an executive model that considers a broad range of parameters at network level maintenance and rehabilitation planning. While having too many details in planning problems makes them more complicated, some restrictions called “technical constraints” were considered to reduce solution time of solving procedure as well as improve M&R activities assignment efficiency. Comparing results of the stochastic model with a deterministic model for a case study revealed that the two‐stage stochastic model led to increased total cost compared to the deterministic one due to considering probability in budgeting. However, the developed model provides several M&R plans that are compatible with budget variation.
Protective Effect of Ethyl Pyruvate against Myocardial Ischemia Reperfusion Injury through Regulations of ROS-Related NLRP3 Inflammasome Activation
Authors: Jun Ji Hae , Shim Jae-Kwang , Oh Ju Eun , Shin Eun-Jung , Shin Eunah , Kwak Young-Lan
Published: January 2019

Emerging evidence indicates the pronounced role of inflammasome activation linked to reactive oxygen species (ROS) in the sterile inflammatory response triggered by ischemia/reperfusion (I/R) injury. Ethyl pyruvate (EP) is an antioxidant and conveys myocardial protection against I/R injury, while the exact mechanisms remain elusive. We aimed to investigate the effect of EP on myocardial I/R injury through mechanisms related to ROS and inflammasome regulation. The rats were randomly assigned to four groups: (1) sham, (2) I/R-control (IRC), (3) EP-pretreatment + I/R, and (4) I/R + EP-posttreatment. I/R was induced by a 30 min ligation of the left anterior descending artery followed by 4 h of reperfusion. EP (50 mg/kg) was administered intraperitoneally at 1 h before ischemia (pretreatment) or upon reperfusion (posttreatment). Both pre- and post-EP treatment resulted in significant reductions in myocardial infarct size (by 34% and 31%, respectively) and neutrophil infiltration. I/R-induced myocardial expressions of NADPH oxidase-4, carnitine palmitoyltransferase 1A, and thioredoxin-interacting protein (TXNIP) were mitigated by EP. EP treatment was associated with diminished inflammasome activation (NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like protein, and caspase-1) and interleukin-1β induced by I/R. I/R-induced phosphorylation of ERK and p38 were also mitigated with EP treatments. In H9c2 cells, hypoxia-induced TXNIP and NLRP3 expressions were inhibited by EP and to a lesser degree by U0126 (MEK inhibitor) and SB203580 (p38 inhibitor) as well. EP’s downstream protective mechanisms in myocardial I/R injury would include mitigation of ROS-mediated NLRP3 inflammasome upregulation and its associated pathways, partly via inhibition of hypoxia-induced phosphorylation of ERK and p38.
MILP Model and a Rolling Horizon Algorithm for Crane Scheduling in a Hybrid Storage Container Terminal
Authors: Yu Kai , Yang Jingcheng
Published: January 2019

This paper investigates the yard crane scheduling problem of a hybrid storage container terminal whose import containers and export containers are stored together in each block. The combination of containers improves the space utilization of a container terminal while it also creates new challenges for the yard crane scheduling. To formulate this problem, we propose a mixed integer linear programming (MILP) model, which jointly optimizes trucks’ waiting costs and penalty costs caused by exceeding waiting time thresholds. Considering the NP‐completeness of this scheduling problem, we develop an efficient rolling horizon algorithm based on some heuristics to reduce the computation time. Finally, computational studies are carried out to evaluate the performance of our method and the solutions obtained by CPLEX solver are used for benchmarking purposes.
Production of Reduced Graphene Oxide Platelets from Graphite Flakes Using the Fenton Reaction as an Alternative to Harmful Oxidizing Agents
Authors: Piñas Jean A. V. , Andrade Tatiana S. , Oliveira Andreia T. , Salomão Pedro E. A. , Rodriguez Mariandry , Silva Adilson C. , Oliveira Henrique S. , Monteiro Douglas S. , Pereira Márcio C.
Published: January 2019

The conventional chemical methods to produce graphene using strong oxidizing agents produce toxic gases during synthesis; therefore, these methods do not meet the principles of green chemistry. In this work, an alternative top-down method for the synthesis of a few layers of graphene sheets has been produced by a Fenton reaction- (a mixture of Fe2+/H2O2) assisted exfoliation process in water using graphite flakes as a starting material. Based on X-ray diffraction data and Fourier transform infrared (FTIR), Raman spectroscopy, and transmission electron microscopy measurements, it is proposed that the oxidation of graphite by Fenton chemistry facilitates the exfoliation of graphene sheets under mild sonication. Subsequent chemical reduction with ascorbic acid produced a few layers of reduced graphene oxide. Compared to Hummers’ method, the Fenton reagent has similar exfoliation efficiency, but due to the Fenton reagent’s preference to react with the edges of graphite, the chemical reduction can lead to the formation of less defective reduced graphene oxides. Moreover, since Fe and H2O2 are cheap and environmentally innocuous, their use in large-scale graphene production is environmentally friendlier than conventional methods that use toxic oxidizing agents.
Valuation of Swing Options under a Regime‐Switching Mean‐Reverting Model
Authors: Shao Lingjie , Xiang Kaili
Published: January 2019

In this paper, we study the valuation of swing options on electricity in a model where the underlying spot price is set to be the product of a deterministic seasonal pattern and Ornstein‐Uhlenbeck process with Markov‐modulated parameters. Under this setting, the difficulties of pricing swing options come from the various constraints embedded in contracts, e.g., the total number of rights constraint, the refraction time constraint, the local volume constraint, and the global volume constraint. Here we propose a framework for the valuation of the swing option on the condition that all the above constraints are nontrivial. To be specific, we formulate the pricing problem as an optimal stochastic control problem, which can be solved by the trinomial forest dynamic programming approach. Besides, empirical analysis is carried out on the model. We collect historical data in Nord Pool electricity market, extract the seasonal pattern, calibrate the Ornstein‐Uhlenbeck process parameters in each regime, and also get market price of risk. Finally, on the basis of calibration results, a specific numerical example concerning all typical constraints is presented to demonstrate the valuation procedure.
Role of Nrf2 and Its Activators in Respiratory Diseases
Authors: Liu Qinmei , Gao Yun , Ci Xinxin
Published: January 2019

Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidant response element- (ARE-) driven cytoprotective protein expression. The activation of Nrf2 signaling plays an essential role in preventing cells and tissues from injury induced by oxidative stress. Under the unstressed conditions, natural inhibitor of Nrf2, Kelch-like ECH-associated protein 1 (Keap1), traps Nrf2 in the cytoplasm and promotes the degradation of Nrf2 by the 26S proteasome. Nevertheless, stresses including highly oxidative microenvironments, impair the ability of Keap1 to target Nrf2 for ubiquitination and degradation, and induce newly synthesized Nrf2 to translocate to the nucleus to bind with ARE. Due to constant exposure to external environments, including diverse pollutants and other oxidants, the redox balance maintained by Nrf2 is fairly important to the airways. To date, researchers have discovered that Nrf2 deletion results in high susceptibility and severity of insults in various models of respiratory diseases, including bronchopulmonary dysplasia (BPD), respiratory infections, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and lung cancer. Conversely, Nrf2 activation confers protective effects on these lung disorders. In the present review, we summarize Nrf2 involvement in the pathogenesis of the above respiratory diseases that have been identified by experimental models and human studies and describe the protective effects of Nrf2 inducers on these diseases.
Evaluation of 3D Nonlinear Earthquake Behaviour of the Ilısu CFR Dam under Far‐Fault Ground Motions
Authors: Karalar Memduh , Çavuşli Murat
Published: January 2019

In the recent times, many huge concrete face rockfill dams (CFRDs) have been modelled and constructed in the world, and many of these dams are located on the strong earthquake zones. Examination of the seismic behaviour of a CFR dam built on the seismic zone is very important to assess the safety and future of the dam. For this reason, the nonlinear earthquake behaviour of these dams should be constantly observed taking into account the seismicity of the zone. In this study, three‐dimensional (3D) seismic behaviour of the Ilısu dam built on the East Anatolian Fault (EAF) line is examined considering the effect of the important various far‐fault earthquakes. The 3D finite difference model of the Ilısu dam is created using the FLAC3D software based on the finite difference method. The dam body, foundation, and concrete slab constantly interact during the lifetime of the CFRDs. Therefore, the special interface elements are defined between the dam body, concrete slab, and foundation to represent the interaction condition. The Mohr–Coulomb nonlinear material model is used for the rockfill materials and foundation. Moreover, the concrete slab is modelled considering the Drucker–Prager nonlinear material model to represent the nonlinearity of the concrete. Very special seismic boundary conditions rarely used for CFR dams in the past are used in this work. These boundary conditions are free‐field and quiet boundary conditions. The free‐field boundary condition that is a very important boundary condition for the nonlinear seismic analyses is considered for the lateral boundaries of the 3D model. In addition, the quiet artificial boundary condition is used for the bottom of the foundation. While defining these boundary conditions, the special fish functions are created and defined to the software. Moreover, the hysteric damping coefficients are separately calculated for all of the materials. These special damping values are defined to the FLAC3D software using the special fish functions to capture the effects of the variation of the modulus and damping ratio with the dynamic shear‐strain magnitude. In the numerical analyses, a total of 7 various strong far‐fault earthquakes are used for the 3D nonlinear earthquake analyses, and 7 different numerical analyses are performed for the full‐reservoir condition of the Ilısu CFR dam. According to the seismic results, the principal stresses for the three critical nodal points on the dam body surface are examined and evaluated in detail. It is clearly understood that the nonlinear seismic behaviour of the Ilısu dam changes depending on the magnitudes and periods of the far‐fault earthquakes. Each far‐fault earthquake has different seismic effects on the nonlinear principal stress behaviour of the Ilısu CFR dam.
A Comparison of Prediction of Adverse Perinatal Outcomes between Hadlock and INTERGROWTH-21stStandards at the Third Trimester
Authors: Zhu Chen , Ren Yun-Yun , Wu Jiang-Nan , Zhou Qiong-Jie
Published: January 2019

Little is known about the clinical value of the Hadlock and INTERGROWTH-21stEFW standards for predicting adverse perinatal outcomes (APOs) in the third trimester. The purpose of this study was to study the association between low estimated fetal weight percentile (EFWc) in the third trimester and the risk of APOs and compare predictions of APOs between Hadlock and INTERGROWTH-21stEFW standards. A prospective cohort of 690 singleton pregnancies with ultrasonography performed in the third trimester between March 2015 and March 2016 in China was conducted. EFW and the corresponding EFWc were measured using the Hadlock and INTERGROWTH-21ststandards, respectively. Cox proportional hazard models were used to assess the relationship between low EFWc (i.e., <5 percentile, P5) and the risk of APOs. Compared with fetuses with ≥P5 of the EFWc, fetuses with <P5 of the EFWc were much more likely to have an APO, with adjusted hazard ratios of 35.0 (95% confidence interval, 13.9-88.5) and 17.5 (7.7-39.6) for the Hadlock and INTERGROWTH standards, respectively. The Hadlock-EFWc had a higher predictive accuracy for APOs than the INTERGROWTH-EFWc, with area under the receiver operating characteristic curve of 0.94 (0.92-0.95) and 0.90 (0.87-0.92), respectively (P=0.007). The cutoff value for the INTERGROWTH-EFWc was percentile 11.61 with a sensitivity and specificity of 87.9% and 80.5%, respectively. For the Hadlock-EFWc, the corresponding sensitivity and specificity were 93.9% and 81.2%, with a cutoff value of percentile 8.65. Fetuses with low EFWc (i.e., <P5) were associated with an increased risk of APOs. APOs were more accurately predicted when EFWc was measured by the Hadlock standard than by the INTERGROWTH-21ststandard.
Oleander Stem and Root Standardized Extracts Mitigate Acute Hyperglycaemia by Limiting Systemic Oxidative Stress Response in Diabetic Mice
Authors: Dey Priyankar , Saha Manas Ranjan , Roy Choudhuri Sumedha , Sarkar Indrani , Halder Biswajit , Poddar-Sarkar Mousumi , Sen Arnab , Chaudhuri Tapas Kumar
Published: January 2019

The extracts of different parts ofNerium oleanderL. are used as antidiabetic remedy in the traditional medicinal systems of different parts of the world. Despite these uses in ethnomedicinal system, the antihyperglycemic potentials of oleander stem (NOSE) and root (NORE) extracts have not been pharmacologically evaluated. Therefore, we aimed at evaluating the antidiabetic ethnomedicinal claims of NOSE and NORE, primarily focusing on glucose homeostasis and associated metabolic implications. Alloxan-treated mice with hyperglycaemia (blood glucose >200 mg/dL) were treated with oleander 70% hydromethanolic extracts (200 mg/kg) for 20 consecutive days, and the results were compared with positive control glibenclamide. Blood glucose level was 52–65% lowered (P<0.001) in oleander treated groups, which was otherwise 4.62 times higher in diabetic mice, compared to control. Insulin resistance was lowered 51–36% irrespective of any significant (P>0.05) changes in insulin sensitivity throughout the treatments. Improved serum insulin remained associated with lowered glucose level (rP = −0.847 and −0.772;P<0.01). Markers of hyperglycaemia-related hepatic glycogen, glycated haemoglobin (HbA1c), hyperlipidaemia, hepatic injury, and diabetic nephropathy were normalized as well. Improvement of systemic intrinsic antioxidant enzymes (catalase and peroxidase) were correlated (rP = −0.952 to −0.773;P<0.01) with lower lipid peroxidation by-product malondialdehyde (MDA) in the circulation. Principal component analysis coupled with hierarchical cluster analysis represented shift in metabolic homeostasis in diabetic mice, which was further normalized by oleander and glibenclamide treatment. Additionally, molecular docking studies of the phenolic acids measured by HPLC with intracellular cytoprotective transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) revealed strong molecular interactions. The results collectively support the ethnomedicine antidiabetic claims of oleander stem and root and suggest that the oleander mediated elevation of systemic antioxidant status is likely responsible for the improved glycaemic control.
Shield Equipment Optimization and Construction Control Technology in Water‐Rich and Sandy Cobble Stratum: A Case Study of the First Yellow River Metro Tunnel Undercrossing
Authors: Ye Fei , Qin Nan , Gao Xiang , Quan Xue-yong , Qin Xian-zhuo , Dai Bing
Published: January 2019

The Lanzhou Yellow River Tunnel is the first metro shield tunnel that undercrosses the Yellow River in China. It was completed after successfully overcoming several construction challenges, including strata with a high proportion of large‐sized sandy cobble stratum being saturated, large‐scale sand pits along the bank of the Yellow River, and a combination of boulders and erratic blocks of rock. Given the difficulties in constructing the tunnel, this paper summarizes the scheme employed to transform the cutter and cutter head design to be applicable to sandy cobble stratum and the key technology used to form the slurry film to facilitate crossing the sand pits in a systematic way. The transformation scheme primarily involved the addition of an adjusting device to control the aperture ratio of the shield on the cutter head, a protective device for the hob hub, and a protective device for the piston rod in the oil cylinder of the crusher. The implementation of measures mentioned above guarantees the safe completion of the tunnel, which can provide a reference for similar projects.
Multiscale Stem Cell Technologies for Osteonecrosis of the Femoral Head
Authors: Wang Yi , Ma Xibo , Chai Wei , Tian Jie
Published: January 2019

The last couple of decades have seen brilliant progress in stem cell therapies, including native, genetically modified, and engineered stem cells, for osteonecrosis of the femoral head (ONFH). In vitro studies evaluate the effect of endogenous or exogenous factor or gene regulation on osteogenic phenotype maintenance and/or differentiation towards osteogenic lineage. The preclinical and clinical outcomes accelerate the clinical translation. Bone marrow mesenchymal stem cells and adipose-derived stem cells have demonstrated better effects in the treatment of femoral head necrosis. Various materials have been used widely in the ONFH treatment in both preclinical and clinical trials. In a word, in vivo and multiscale efforts are expected to overcome obstacles in the approaches for treating ONFH and provide clinical relevance and commercial strategies in the future. Therefore, we will discuss the above aspects in this paper and present our opinions.
Rate of Drug Coating Dissolution Determines In-Tissue Drug Retention and Durability of Biological Efficacy
Authors: Granada Juan F. , Virmani Renu , Schulz-Jander Daniel , Tunev Stefan , Melder Robert J.
Published: January 2019

Two different drug-coated balloons (DCBs) possessing different coating formulations were compared for rate of coating dissolution in vitro, in addition to tissue drug concentration and histological responses of treated vascular tissue in vivo, to determine if the rate of drug bioavailability to vascular tissue can impact the degree and duration of the observed pharmacological response to locally delivered drug. In vitro dissolution comparison demonstrated that a urea/paclitaxel-based coating formulation (IN.PACT™ Admiral™) released drug from solid to soluble phase at a slower and constant rate, yielding approximately 7% solubilized drug in 24 h. In contrast, a coating formulated from polysorbate/sorbitol/paclitaxel (Lutonix™) released 51% of solid phase drug to soluble phase in 1 h of dissolution with the remainder solubilizing in 24 h. In vivo evaluation of tissue drug concentration of both products showed significantly different tissue pharmacokinetic profile, with a higher concentration of paclitaxel in tissue at 90 days with a urea-based formulation excipient. Histological comparison of smooth muscle cell loss in response to drug exposure revealed contrasting trends of smooth muscle cell loss from 28 to 90 days with significantly higher response to drug observed at 90 days with the urea-based formulation. Rapid dissolution of drug from the polysorbate/sorbitol coating formulation was associated with an early increase in local cellular response to drug which diminished over 90 days with clearance of local drug from tissue. Sustained long-term drug-in-tissue concentration associated with the urea-based formulation demonstrated sustained pharmacological activity at 90 days, suggesting that slow coating dissolution provides a sustainable long-term tissue response.
Molecular Dynamics Simulations of A27S and K120A Mutated PTP1B Reveals Selective Binding of the Bidentate Inhibitor
Authors: Chen Xi , Liu Xia , Gan Qiang , Feng Changgen , Zhang Qian
Published: January 2019

Protein tyrosine phosphatase 1B (PTP1B) is considered a potential target for the treatment of type II diabetes and obesity due to its critical negative role in the insulin signaling pathway. However, improving the selectivity of PTP1B inhibitors over the most closely related T-cell protein tyrosine phosphatase (TCPTP) remains a major challenge for inhibitor development. Lys120 at the active site and Ser27 at the second pTyr binding site are distinct in PTP1B and TCPTP, which may bring differences in binding affinity. To explore the determinant of selective binding of inhibitor, molecular dynamics simulations with binding free energy calculations were performed on K120A and A27S mutated PTP1B, and the internal changes induced by mutations were investigated. Results reveal that the presence of Lys120 induces a conformational change in the WPD-loop and YRD-motif and has a certain effect on the selective binding at the active site. Ser27 weakens the stability of the inhibitor at the second pTyr binding site by altering the orientation of the Arg24 and Arg254 side chains via hydrogen bonds. Further comparison of alanine scanning demonstrates that the reduction in the energy contribution of Arg254 caused by A27S mutation leads to a different inhibitory activity. These observations provide novel insights into the selective binding mechanism of PTP1B inhibitors to TCPTP.
Mechanochemical Disruption Suppresses Metastatic Phenotype and Pushes Prostate Cancer Cells toward Apoptosis
Authors: Murad Hakm Y. , Yu Heng , Luo Daishen , Bortz Emma P. , Halliburton Gray M. , Sholl Andrew B. , Khismatullin Damir B.
Published: January 2019

Chemical-based medicine that targets specific oncogenes or proteins often leads to cancer recurrence due to tumor heterogeneity and development of chemoresistance. This challenge can be overcome by mechanochemical disruption of cancer cells via focused ultrasound (FUS) and sensitizing chemical agents such as ethanol. We demonstrate that this disruptive therapy decreases the viability, proliferation rate, tumorigenicity, endothelial adhesion, and migratory ability of prostate cancer cells in vitro. It sensitized the cells to TNFR1-- and Fas--mediated apoptosis and reduced the expression of metastatic markers CD44 and CD29. Using a prostate cancer xenograft model, we observed that the mechanochemical disruption led to complete tumor regression in vivo. This switch to a nonaggressive cell phenotype was caused by ROS and Hsp70 overproduction and subsequent impairment of NFκB signaling. FUS induces mechanical perturbations of diverse cancer cell populations, and its combination with agents that amplify and guide remedial cellular responses can stop lethal cancer progression.

Implications:

Mechanochemical disruption therapy in which FUS is combined with ethanol can be curative for locally aggressive and castration-resistant prostate cancer.
Comparison of Efficacy between Internal Iliac Artery and Abdominal Aorta Balloon Occlusions in Pernicious Placenta Previa Patients with Placenta Accrete
Authors: Wei Yan , Luo Jianru , Luo Dan
Published: January 2019

Background: We aimed to compare the hemostatic effect and perioperative outcomes between internal iliac artery (IIA) and abdominal aorta (AA) balloon occlusions in pernicious placenta previa patients complicated with placenta accrete and underwent cesarean delivery. Methods: One hundred and twenty-three pernicious placenta previa patients complicated with placenta accrete were retrospectively reviewed. Patients who received IIA or AA occlusions were subsequently divided into the IIA group (n = 71) and AA group (n = 52). Estimated blood loss (EBL) and blood transferring volume were evaluated. Results: No difference was observed in EBL during cesarean delivery, EBL within 24 h or blood transferring volume between IIA and AA groups. Subgroup analysis disclosed that AA occlusion presented lower EBL during cesarean delivery and EBL within 24 h compared to IIA occlusion in placenta percreta subgroup. For secondary outcomes, IIA occlusion caused better Apgar score at 1 min but higher rates of IIA ligation and iodoform gauze packing of the uterine cavity compared to AA occlusion. Multivariate linear analysis revealed that invasion depth independently predicted worse EBL. Conclusion: IIA and AA occlusions have similar hemostatic effects in pernicious placenta previa patients with placenta accrete underwent cesarean delivery, while AA occlusion is more effective in reducing EBL in placenta percreta subgroup.
Lamellar Macular Hole: State of the Art
Authors: Frisina Rino , Pilotto Elisabetta , Midena Edoardo
Published: January 2019

Lamellar macular hole (LMH) is a vitreoretinal disorder characterized by an irregular foveal contour, a break in the inner fovea, dehiscence of the inner foveal retina from the outer retina, and the absence of a full-thickness foveal defect with intact foveal photoreceptors. The pathogenesis is only partially known. The advent of high-resolution optical coherence tomography has allowed distinguishing between two types of epiretinal membrane (ERM) associated with LMH: a conventional ERM (commonly found in macular pucker) and an atypical ERM (known by varied names: dense, epiretinal proliferation, or degenerative). These two types of ERM not only influence LMH morphology but also differ in cell and collagen composition. It remains unclear if these two types are indeed two distinct clinical entities or rather two stages of the same macular disorder. Studies of the natural evolution of LMH have not fully resolved this issue and also offered variable results. Surgical treatment leads to excellent anatomical and functional outcomes, but not without risks. This review provides a critical summary of the available data on LMH including some new insights.
Unilateral Thalamic Deep Brain Stimulation for Voice Tremor
Authors: Avecillas-Chasin Josue M. , Poologaindran Anujan , Morrison Murray D. , Rammage Linda A. , Honey Christopher R.
Published: January 2019

Background: Voice tremor (VT) is the involuntary and rhythmical phonatory instability of the voice. Recent findings suggest that unilateral deep brain stimulation of the ventral intermediate nucleus (Vim-DBS) can sometimes be effective for VT. In this exploratory analysis, we investigated the effect of Vim-DBS on VT and tested the hypothesis that unilateral thalamic stimulation is effective for patients with VT. Methods: Seven patients with VT and previously implanted bilateral Vim-DBS were enrolled in the study. Each patient was randomized and recorded performing sustained phonation during the following conditions: left thalamic stimulation, right thalamic stimulation, bilateral thalamic stimulation (Bil-ON), and no stimulation (Bil-OFF). Perceptual VT ratings and an acoustic analysis to find the rate of variation of the fundamental frequency measured by the standard deviation of the pitch (f0SD) were performed in a blinded manner. For the purposes of this study, a “dominant” side was defined as one with more than twice as much reduction in VT following Vim-DBS compared to the contralateral side. The Wilcoxon signed-rank test was performed to compare the effect of the dominant side stimulation in the reduction of VT scores and f0SD. The volume of activated tissue (VAT) of the dominant stimulation side was modelled against the degree of improvement in VT to correlate the significant stimulation cluster with thalamic anatomy. Finally, tractography analysis was performed to analyze the connectivity of the significant stimulation cluster. Results: Unilateral stimulation was beneficial in all 7 patients. Five patients clearly had a “dominant” side with either benefit only seen following stimulation of one side or more than twice as much benefit from one side compared to the other. Two patients had similar benefit with unilateral stimulation from either side. The Wilcoxon paired test showed significant differences between unilateral dominant and unilateral nondominant stimulation for VT scores (p = 0.04), between unilateral dominant and Bil-OFF (p = 0.04), and between Bil-ON and unilateral nondominant stimulation (p = 0.04). No significant differences were found between Bil-ON and unilateral dominant condition (p = 0.27), or between Bil-OFF and unilateral nondominant (p = 0.23). The dominant VAT showed that the significant voxels associated with the best VT control were located in the most ventral and medial part of the Vim nucleus and the ventralis caudalis anterior internus nucleus. The connectivity analysis showed significant connectivity with the cortical areas of the speech circuit. Conclusions: Unilateral dominant-side thalamic stimulation and bilateral thalamic stimulation were equally effective in reducing VT. Nondominant unilateral stimulation alone did not significantly improve VT.
Smoking and Obesity as Risk Factors in Frontotemporal Dementia and Alzheimer’s Disease: The HUNT Study
Authors: Rasmussen Eid Hege , Rosness Tor Atle , Bosnes Ole , Salvesen Øyvind , Knutli Marlen , Stordal Eystein
Published: January 2019

Background: Few studies have assessed smoking and obesity together as risk factors for frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Objective: To study smoking and obesity as risk factors for FTD and AD. Methods: Ninety patients with FTD and 654 patients with AD were compared with 116 cognitively healthy elderly individuals in a longitudinal design with 15–31 years between measurements of risk factors before the dementia diagnosis. Results: There were no associations between smoking and FTD (p = 0.218; odds ratio [OR]: 0.990; 95% confidence interval [CI]: 0.975–1.006). There were significant associations between obesity and FTD (p = 0.049; OR: 2.629; 95% CI: 1.003–6.894). There were significant associations between both smoking (p = 0.014; OR: 0.987; 95% CI: 0.977–0.997) and obesity (p = 0.015; OR: 2.679; 95% CI: 1.211–5.928) and AD. Conclusion: Our findings suggest that obesity is a shared risk factor for FTD and AD, while smoking plays various roles as a risk factor for FTD and AD.
Intravenous Misuse of Methadone, Buprenorphine and Buprenorphine-Naloxone in Patients Under Opioid Maintenance Treatment: A Cross-Sectional Multicentre Study
Authors: Lugoboni Fabio , Zamboni Lorenzo , Cibin Mauro , Tamburin Stefano ,   Gruppo InterSERT di Collaborazione Scientifica (GICS)
Published: January 2019

Background: The act of intravenous misuse is common in patients under opioid maintenance treatment (OMT), but information on associated factors is still limited. Objectives: To explore factors associated with (a) intravenous OMT misuse, (b) repeated misuse, (c) emergency room (ER) admission, (d) misuse of different OMT types and (e) concurrent benzodiazepine misuse. Methods: We recruited 3,620 patients in 27 addiction units in Italy and collected data on the self-reported rate of intravenous injection of methadone (MET), buprenorphine (BUP), BUP-naloxone (NLX), OMT dosage and type, experience of and reason for misuse, concurrent intravenous benzodiazepine misuse, pattern of ­misuse in relation to admission to the addiction unit and ER ­admissions because of misuse. According to inclusion/exclusion criteria, 2,585 patients were included. Results: Intravenous misuse of OMT substances was found in 28% of patients with no difference between OMT types and was associated with gender, age, type of previous opioid abuse and intravenous benzodiazepine misuse. Repeated OMT misuse was reported by 20% (i.e., 71% of misusers) of patients and was associated with positive OMT misuse experience and intravenous benzodiazepine misuse. Admission to the ER because of misuse complications was reported by 34% of patients, this outcome being associated with gender, employment, type of previous opioid abuse and intravenous benzodiazepine misuse. OMT dosage was lower than the recommended maintenance dosage. Conclusions: We offered new information on factors associated with intravenous OMT misuse, repeated misuse and ER admission in Italian patients under OMT. Our data indicate that BUP-NLX misuse is not different from that of BUP or MET. Choosing the more expensive BUP-NLX over MET will likely not lead to the expected reduction of the risk of injection misuse of the OMT. Instead of prescribing new and expensive OMT formulations, addiction unit physicians and medical personnel should better focus on patient’s features that are associated with a higher likelihood of misuse. Care should be paid to concurrent benzodiazepine and OMT misuse.
Substance Abuse-Related Self-Stigma in Women with Substance Use Disorder and Comorbid Posttraumatic Stress Disorder
Authors: Melchior Hanne , Hüsing Paul , Grundmann Johanna , Lotzin Annett , Hiller Philipp , Pan Yiqi , Driessen Martin , Scherbaum Norbert , Schneider Barbara , Hillemacher Thomas , Stolzenburg Susanne , Schomerus Georg , Schäfer Ingo ,   Cansas Study Group
Published: January 2019

Background: Self-stigma is a result of internalizing negative stereotypes by the affected person. Research on self-stigma in substance use disorders (SUD) is still scarce, especially regarding the role of childhood trauma and subsequent posttraumatic disorders. Objectives: The present study investigated the progressive model of self-stigma in women with SUD and posttraumatic stress disorder (PTSD), and the predictive value of PTSD severity and childhood trauma experiences on self-stigma. Method: In a cross-sectional study with 343 women with SUD and PTSD, we used the Self-Stigma in Alcohol Dependency Scale, the Childhood Trauma Questionnaire (CTQ), the PTSD Symptom Scale Interview (PSS-I), and to control for SUD severity and depression, the Addiction Severity Index Lite and the Beck Depression Inventory-II. Hierarchical regression analyses were conducted for each stage of self-stigma (aware-agree-apply-harm). Results: The interrelated successive stages of self-stigma were largely confirmed. In the regression models, no significant effects of the PSS-I- and the CTQ-scores were observed at any stage of self-stigma. Agreeing with negative stereotypes was solely predicted by younger age, applying these stereotypes to oneself was higher in women with younger age, higher depression and SUD severity, and suffering from the application (harm) was only predicted by depression. Conclusions: The progressive model of self-stigma could be confirmed in women with SUD and PTSD, but PTSD severity and childhood trauma did not directly affect this process. Self-stigma appears to be related to depression in a stronger way than PTSD is related to women with SUD and PTSD.