bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distorted vacuum black holes in the canonical ensemble
Authors: Zaslavskii O. B. 
Published: March 2019

We consider a vacuum static spacetime in a finite size cavity. On the boundary, we specify a metric and a finite constant local temperature [Formula: see text]. No spherical or any other spatial symmetry is assumed. We show that (i) inside a cavity, only a black hole or flat spacetime are possible, whereas a curved horizonless regular spacetime is excluded, (ii) in the limit when the horizon area shrinks, the Hawking temperature diverges, (iii) for the existence of a black hole, [Formula: see text] should be high enough. When [Formula: see text], a black hole phase is favorable thermodynamically. Our consideration essentially uses the coordinate system introduced by Israel in his famous proof of the uniqueness theorem.
Identify Severity Bug Report with Distribution Imbalance by CR-SMOTE and ELM
Authors: Guo Shikai , Chen Rong , Li Hui , Zhang Tianlun , Liu Yaqing 
Published: March 2019

Manually inspecting bugs to determine their severity is often an enormous but essential software development task, especially when many participants generate a large number of bug reports in a crowdsourced software testing context. Therefore, boosting the capabilities of methods of predicting bug report severity is critically important for determining the priority of fixing bugs. However, typical classification techniques may be adversely affected when the severity distribution of the bug reports is imbalanced, leading to performance degradation in a crowdsourcing environment. In this study, we propose an enhanced oversampling approach called CR-SMOTE to enhance the classification of bug reports with a realistically imbalanced severity distribution. The main idea is to interpolate new instances into the minority category that are near the center of existing samples in that category. Then, we use an extreme learning machine (ELM) — a feedforward neural network with a single layer of hidden nodes — to predict the bug severity. Several experiments were conducted on three datasets from real bug repositories, and the results statistically indicate that the presented approach is robust against real data imbalance when predicting the severity of bug reports. The average accuracies achieved by the ELM in predicting the severity of Eclipse, Mozilla, and GNOME bug reports were 0.780, 0.871, and 0.861, which are higher than those of classifiers by 4.36%, 6.73%, and 2.71%, respectively.
Further improvement on bounds for L-functions related to GL(3)
Authors: Sun Haiwei , Ye Yangbo 
Published: March 2019

Let [Formula: see text] be a fixed self-dual Hecke–Maass form for [Formula: see text], and let [Formula: see text] be an even Hecke–Maass form for [Formula: see text] with Laplace eigenvalue [Formula: see text], [Formula: see text]. A subconvexity bound for [Formula: see text] is improved to [Formula: see text], and a subconvexity bound for [Formula: see text] is improved to [Formula: see text]. New techniques employed include an application of an asymptotic formula by Salazar and Ye [Spectral square moments of a resonance sum for Maass forms, Front. Math. China 12(5) (2017) 1183–1200] to make error terms negligible, an iterative algorithm to locate stationary point, and a non-trivial estimation of Kloosterman sums.
Respiratory Capacity and Reserve Predict Cell Sensitivity to Mitochondria Inhibitors: Mechanism-Based Markers to Identify Metformin-Responsive Cancers
Authors: Teh Jing Tsong , Zhu Wan Long , Newgard Christopher B. , Casey Patrick J. , Wang Mei 
Published: March 2019

Abstract
Metformin has been extensively studied for its impact on cancer cell metabolism and anticancer potential. Despite evidence of significant reduction in cancer occurrence in diabetic patients taking metformin, phase II cancer trials of the agent have been disappointing, quite possibly because of the lack of molecular mechanism-based patient stratification. In an effort to identify cancers that are responsive to metformin, we discovered that mitochondria respiratory capacity and respiratory reserve, which vary widely among cancer cells, correlate strongly to metformin sensitivity in both the in vitro and in vivo settings. A causal relationship between respiratory function and metformin sensitivity is demonstrated in studies in which we lowered respiratory capacity by either genetic knockdown or pharmacologic suppression of electron transport chain components, rendering cancer cells more vulnerable to metformin. These findings led us to predict, and experimentally validate, that metformin and AMP kinase inhibition synergistically suppress cancer cell proliferation.
Reduction of Muscle-Invasive Tumors by Photodynamic Therapy with Tetrahydroporphyrin-Tetratosylat in an Orthotopic Rat Bladder Cancer Model
Authors: Berndt-Paetz Mandy , Schulze Philipp , Stenglein Philipp C. , Weimann Annett , Wang Qiang , Horn Lars-Christian , Riyad Yasser M. , Griebel Jan , Hermann Ralf , Glasow Annegret , Stolzenburg Jens-Uwe , Neuhaus Jochen 
Published: March 2019

Abstract
Photodynamic therapy (PDT) is a promising option for minimal-invasive treatment of bladder cancer. Efficacy of PDT in muscle-invasive urothelial cancer is still hampered by low tissue penetration of most photosensitizers due to short excitation wavelength. The novel light reactive agent tetrahydroporphyrin-tetratosylat (THPTS) is excitable at near-infrared (760 nm), allowing tissue penetration of up to 15 mm. Here, we established an orthotopic rat bladder cancer model and examined the effects of THPTS-PDT on tumor growth in vivo, and analyzed molecular mechanisms in vitro. We examined pharmacokinetics and subcellular localization, and evoked cell death mode in cultured rat urothelial carcinoma cells (AY-27). We used female F344 Fischer rats for in vivo studies. Ten rats each were used for THPTS-PDT and light-only control. Bladders were evaluated by macroscopy and histology. Temperature-dependent THPTS uptake resulted in endosomal/lysosomal localization. PDT (0–50 μmol/L THPTS; 10 J/cm2) induced early onset of apoptosis leading to dose-dependent cytotoxicity in AY-27 cells. Single-time transurethral THPTS-PDT (100 μmol/L THPTS; 10 J/cm2) in F344 rats led to significant reduction of muscle-invasive tumor number (2/10 vs. 7/10 in controls) and total tumor volume (60% reduction) 2 weeks after PDT, while sparing healthy tissue. Here, we report for the first time effective tumor growth control by PDT in vivo. THPTS is a promising new photosensitizer with the advantage of higher therapeutic depth and the potential of high-selective therapy in muscle-invasive urothelial cancer. This approach possibly allows minimal-invasive bladder preserving treatment of bladder cancer without systemic side effects.
Targeting Apoptosis: A New Paradigm for the Treatment of Estrogen Receptor–Positive Breast Cancer
Authors: Drago Joshua Z. , Chandarlapaty Sarat , Jhaveri Komal 
Published: March 2019

Abstract

Summary:
Standard treatment for estrogen receptor–positive metastatic breast cancer involves antiestrogen therapy used alone or in combination with inhibitors of CDK4/6 or mTOR; this approach works mechanistically by eliciting and reinforcing cell-cycle arrest. In this issue, Lok and colleagues diverge from this paradigm by combining the BCL2 inhibitor venetoclax with tamoxifen in a phase Ib clinical trial, building on preclinical work to demonstrate that targeting apoptosis could represent a promising new strategy in the treatment of breast cancer.
See related article by Lok et al., p. 354.
Fibroblast Primary Cilia Are Required for Cardiac Fibrosis
Authors: Villalobos Elisa , Criollo Alfredo , Schiattarella Gabriele G. , Altamirano Francisco , French Kristin M. , May Herman I. , Jiang Nan , Nguyen Ngoc Uyen Nhi , Romero Diego , Roa Juan Carlos , García Lorena , Diaz-Araya Guillermo , Morselli Eugenia , Ferdous Anwarul , Conway Simon J. , Sadek Hesham A. , Gillette Thomas G. , Lavandero Sergio , Hill Joseph A. 
Published: March 2019

Background:
The primary cilium is a singular cellular structure that extends from the surface of many cell types and plays crucial roles in vertebrate development, including that of the heart. Whereas ciliated cells have been described in developing heart, a role for primary cilia in adult heart has not been reported. This, coupled with the fact that mutations in genes coding for multiple ciliary proteins underlie polycystic kidney disease, a disorder with numerous cardiovascular manifestations, prompted us to identify cells in adult heart harboring a primary cilium and to determine whether primary cilia play a role in disease-related remodeling.

Methods:
Histological analysis of cardiac tissues from C57BL/6 mouse embryos, neonatal mice, and adult mice was performed to evaluate for primary cilia. Three injury models (apical resection, ischemia/reperfusion, and myocardial infarction) were used to identify the location and cell type of ciliated cells with the use of antibodies specific for cilia (acetylated tubulin, γ-tubulin, polycystin [PC] 1, PC2, and KIF3A), fibroblasts (vimentin, α-smooth muscle actin, and fibroblast-specific protein-1), and cardiomyocytes (α-actinin and troponin I). A similar approach was used to assess for primary cilia in infarcted human myocardial tissue. We studied mice silenced exclusively in myofibroblasts for PC1 and evaluated the role of PC1 in fibrogenesis in adult rat fibroblasts and myofibroblasts.

Results:
We identified primary cilia in mouse, rat, and human heart, specifically and exclusively in cardiac fibroblasts. Ciliated fibroblasts are enriched in areas of myocardial injury. Transforming growth factor β-1 signaling and SMAD3 activation were impaired in fibroblasts depleted of the primary cilium. Extracellular matrix protein levels and contractile function were also impaired. In vivo, depletion of PC1 in activated fibroblasts after myocardial infarction impaired the remodeling response.

Conclusions:
Fibroblasts in the neonatal and adult heart harbor a primary cilium. This organelle and its requisite signaling protein, PC1, are required for critical elements of fibrogenesis, including transforming growth factor β-1–SMAD3 activation, production of extracellular matrix proteins, and cell contractility. Together, these findings point to a pivotal role of this organelle, and PC1, in disease-related pathological cardiac remodeling and suggest that some of the cardiovascular manifestations of autosomal dominant polycystic kidney disease derive directly from myocardium-autonomous abnormalities.
Native Coronary Collateral Microcirculation Reserve in Rat Hearts
Authors: Liu Xiucheng , Dong Hongyan , Huang Bing , Miao Haoran , Xu Zhiwei , Yuan Yanliang , Qiu Fan , Chen Jiali , Zhang Hao , Liu Zhiwei , Quan Xiaoyu , Zhu Lidong , Zhang Zhongming 
Published: March 2019

Background
We occasionally noticed that native collateral blood flow showed a recessive trend in the early stages of acute myocardial infarction in rats, which greatly interferes with the accurate assessment of native collateral circulation levels. Here, we sought to recognize the coronary collateral circulation system in depth, especially the microcirculation part, on this basis.

Methods and Results
In this study, we detected native collateral flow with positron emission tomography perfusion imaging in rats and found that the native flow is relatively abundant when it is initially recruited. However, this flow is extremely unstable in the early stage of acute myocardial infarction and quickly fails. We used tracers to mark the collateral in an ischemic area and a massive preformed collateral network was labeled. The ultrastructures of these collateral microvessels are flawed, which contributes to extensive leakage and consequent interstitial edema in the ischemic region.

Conclusions
An unrecognized short‐lived native coronary collateral microcirculation reserve is widely distributed in rat hearts. Recession of collateral blood flow transported by coronary collateral microcirculation reserve contributes to instability of native collateral blood flow in the early stage of acute myocardial infarction. The immature structure determines that these microvessels are short‐lived and provide conditions for the development of early interstitial edema in acute myocardial infarction.
Influence of 2‐Methoxyestradiol and Sex on Hypoxia‐Induced Pulmonary Hypertension and Hypoxia‐Inducible Factor‐1‐α
Authors: Docherty Craig K. , Nilsen Margaret , MacLean Margaret R. 
Published: March 2019

Background

Women are at greater risk of developing pulmonary arterial hypertension, with estrogen and its downstream metabolites playing a potential role in the pathogenesis of the disease.
Hypoxia‐inducible factor‐1‐α (HIF
1α) is a pro‐proliferative mediator and may be involved in the development of human
pulmonary arterial hypertension
. The estrogen metabolite 2‐methoxyestradiol (2
ME
2) has antiproliferative properties and is also an inhibitor of
HIF
1α. Here, we examine sex differences in
HIF
1α signaling in the rat and human pulmonary circulation and determine if 2
ME
2 can inhibit
HIF
1α in vivo and in vitro.

Methods and Results

HIF
1α signaling was assessed in male and female distal human pulmonary artery smooth muscle cells (
hPASMC
s), and the effects of 2
ME
2 were also studied in female
hPASMC
s. The in vivo effects of 2
ME
2 in the chronic hypoxic rat (male and female) model of pulmonary hypertension were also determined. Basal
HIF
1α protein expression was higher in female
hPASMC
s compared with male. Both factor‐inhibiting
HIF
and
prolyl hydroxylase‐2
(hydroxylates
HIF
leading to proteosomal degradation) protein levels were significantly lower in female
hPASMC
s when compared with males. In vivo, 2
ME
2 ablated hypoxia‐induced pulmonary hypertension in male and female rats while decreasing protein expression of
HIF
1α. 2
ME
2 reduced proliferation in
hPASMC
s and reduced basal protein expression of
HIF
1α. Furthermore, 2
ME
2 caused apoptosis and significant disruption to the microtubule network.

Conclusions

Higher basal
HIF
1α in female
hPASMC
s may increase susceptibility to developing
pulmonary arterial hypertension
. These data also demonstrate that the antiproliferative and therapeutic effects of 2
ME
2 in pulmonary hypertension may involve inhibition of
HIF
1α and/or microtubular disruption in
PASMC
s.
Can Lagrangian Tracking Simulate Tracer Spreading in a High-Resolution Ocean General Circulation Model?
Authors: Wagner Patrick , Rühs Siren , Schwarzkopf Franziska U. , Koszalka Inga Monika , Biastoch Arne 
Published: March 2019

AbstractTo model tracer spreading in the ocean, Lagrangian simulations in an offline framework are a practical and efficient alternative to solving the advective–diffusive tracer equations online. Differences in both approaches raise the question of whether both methods are comparable. Lagrangian simulations usually use model output averaged in time, and trajectories are not subject to parameterized subgrid diffusion, which is included in the advection–diffusion equations of ocean models. Previous studies focused on diffusivity estimates in idealized models but could show that both methods yield similar results as long as the deformations-scale dynamics are resolved and a sufficient amount of Lagrangian particles is used. This study compares spreading of an Eulerian tracer simulated online and a cloud of Lagrangian particles simulated offline with velocities from the same ocean model. We use a global, eddy-resolving ocean model featuring 1/20° horizontal resolution in the Agulhas region around South Africa. Tracer and particles were released at one time step in the Cape Basin and below the mixed layer and integrated for 3 years. Large-scale diagnostics, like mean pathways of floats and tracer, are almost identical and 1D horizontal distributions show no significant differences. Differences in vertical distributions, seen in a reduced vertical spreading and downward displacement of particles, are due to the combined effect of unresolved subdaily variability of the vertical velocities and the spatial variation of vertical diffusivity. This, in turn, has a small impact on the horizontal spreading behavior. The estimates of eddy diffusivity from particles and tracer yield comparable results of about 4000 m2 s−1 in the Cape Basin.
Association of high mobility group box 1 protein with coronary artery disease
Authors: Benlier Necla , Erdoğan Mustafa Bilge , Keçioğlu Serdar , Orhan Nuri , Çiçek Hülya 
Published: March 2019

Background Recently, the role of inflammation in coronary artery disease and the association of inflammatory biomarkers with adverse outcomes have been investigated in many studies. We investigated the relationship between high serum mobility group box 1 protein levels and established risk factors for coronary artery disease. Methods Fifty-five patients who presented to our Cardiovascular Surgery Clinic and subsequently underwent coronary artery bypass surgery for coronary artery disease and 50 healthy subjects presenting to the cardiology outpatient clinic without any cardiovascular problem were included in the study. The mean age was 61.47 ± 9.38 years for patients and 58.20 ± 10.15 years for controls. Results There was no statistically significant difference between groups with respect to age or sex. Family history of coronary artery disease, aspirin use, hypertension, and type 2 diabetes were significantly more prevalent in the patient group versus the control group. A significant difference was found between patients and healthy controls with respect to high mobility group box 1 protein levels ( p = 0.001). Conclusions Serum high mobility group box 1 protein was significantly increased in patients with coronary artery disease in comparison to healthy subjects. No associations were found between high mobility group box 1 protein level and certain risk factors for coronary artery disease.
Perfusion strategy and mid-term results of 58 consecutive pulmonary endarterectomy
Authors: Yan Shujie , Lou Song , Zhu Jiade , Liu Sheng , Zhao Yu , Song Yunhu , Wang Hui , Ji Bingyang 
Published: March 2019

Objective: The aim of this retrospective study was to review and report short-term and mid-term outcomes of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension at our institute in the recent 2 years and to describe perfusion strategy. Methods: A total of 58 consecutive patients with chronic thromboembolic pulmonary hypertension underwent pulmonary endarterectomy under deep hypothermia circulatory arrest with an established perfusion practice between November 2015 and December 2017. Peri-operative data and patients’ outcome were retrospectively analyzed. Results: Mean pulmonary artery pressure was decreased (49 (40-56) mmHg vs 27 (20-31) mmHg, p < 0.001), and pulmonary vascular resistance (724 (538-1108) vs 206 (141-284) dyn second cm−5, p < 0.001) improved significantly after surgery. In-hospital mortality was 1.7% and postoperative complication rate was 27.6%. Antipsychotic medication of olanzapine was prescribed for 36 patients (62.1%), which was independently related to total deep hypothermic circulatory arrest time, postoperative blood potassium concentration, and hematocrit. The majority of patients recovered uneventfully with good mid-term cardiac function (New York Heart Association I-II: 98.1%) and neurological outcome (Glasgow Outcome Scale—Extended Upper Good Recovery: 74.1% and Lower Good Recovery: 20.3%). Mid-term neurological outcome was associated with post–pulmonary endarterectomy antipsychotic medication. Conclusion: Short-term and mid-term outcome after pulmonary endarterectomy was comparable to high-volume centers. Incidence of post–pulmonary endarterectomy delirium was relatively high and associated with mid-term neurological outcome. Total deep hypothermic circulatory arrest time, postoperative blood potassium concentration, and hematocrit were independent risk factors of postoperative olanzapine medication. More efforts and further research are required to optimize the neuroprotection of perfusion practice.
Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using CRISPR/Cas9 and single-stranded donor oligonucleotides
Authors: Dong Yunpeng , Peng Tao , Wu Weijing , Tan Donghui , Liu Xuezhong , Xie Dinghua 
Published: March 2019

Background Heterozygous purinergic receptor p2x gene ( P2RX2) c.178G>T (p.V60L) mutations can lead to progressive hearing loss (HL) and increased susceptibility to noise. However, the underlying mechanisms remain unclear. A combination of human induced pluripotent stem cell (hiPSC) technology with clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9-mediated gene editing may provide a promising tool to study gene function and treat hereditary deafness in humans. Methods hiPSC technology and CRISPR/Cas9-mediated gene editing were used to generate heterozygous and homozygous P2RX2 c.178G>T (p.V60L) cell models. Results We generated non-integrative hiPSCs from urine samples derived from three members of a large Chinese family carrying heterozygous P2RX2 c.178G>T mutations (designated P2RX2+/–) as a model to study P2RX2-mediated hereditary HL. Furthermore, we used CRISPR/Cas9 and single-stranded donor oligonucleotides to genetically establish homozygous P2RX2 c.178G>T hiPSCs (designated P2RX2–/–) from heterozygous patient-specific hiPSCs as a control to further study the pathological gene function. Conclusions Heterozygous and homozygous P2RX2-mutated hiPSC lines are good models to investigate the pathological mechanisms of P2RX2 mutations in HL pathogenesis. Our findings confirmed our hypothesis that it is feasible and convenient to introduce precise point mutations into genomic loci of interest to generate gene-mutated hiPSC models.
Long-term treatment patterns of prophylactic and acute migraine medications and incidence of opioid-related adverse events in patients with migraine
Authors: Bonafede Machaon , Wilson Kathleen , Xue Fei 
Published: March 2019

ObjectivesTo describe long-term treatment patterns in migraine patients initiating prophylactic therapy and to evaluate acute medication use and adverse events associated with opioids.MethodsThis study used the 2005–2014 IBM MarketScan® databases to evaluate migraine patients initiating prophylactic medication. Outcome measures included persistence with prophylactic migraine medications over 2–5 years. Acute medication use and gastrointestinal-related adverse events and opioid abuse following opioid use were evaluated. Cox proportional hazards models were used to evaluate predictors of non-persistence and predictors of gastrointestinal-related AEs and opioid abuse associated with long-term opioid use.ResultsIn total, 147,832 patients were analyzed. Non-persistence was observed in 90% of patients; 39% switched, 30% restarted, and 31% discontinued treatment. Over the follow-up, 59.9% of patients received triptans, 66.6% non-steroidal anti-inflammatory drugs, 77.4% opioids, and 2.6% ergotamines. Among opioid users, 16.6% experienced nausea/vomiting, 12.2% had constipation, and 10.4% had diarrhea. Opioid abuse was reported in <1% of opioid users. Gastrointestinal-related adverse events increased with increasing number of days’ supply of opioids.ConclusionsNon-persistence to prophylactic treatment was frequent among migraine patients. Opioid use was common in migraine patients and the risk of gastrointestinal-related adverse events and opioid abuse increased with long-term use of opioids. These results suggest a need for more effective prophylactic migraine treatments.