bluuebunny/crossref_metadata_2025 huggingface dataset:
Preservation of carbon isotopes in kerogen from thermally altered Mesoproterozoic lacustrine microbialites
Authors: Osterhout Jeffrey T. , Czaja Andrew D. , Bartley Julie K. , Fralick Philip W.
Published: March 2019

Stable carbon isotope geochemistry is a well-established and reliable tool for studying metabolisms of microbial communities in the Precambrian record; however, the isotopic effects of high-temperature alteration from igneous intrusions (i.e., contact metamorphism) have not been thoroughly explored. The Mesoproterozoic (∼1.4 Ga) Middlebrun Bay Member of the Rossport Formation, Sibley Group, in Ontario, Canada, is composed of carbonaceous stromatolites and microbial laminites preserved in an evaporitic, lacustrine chert–carbonate deposit and is cross-cut by an intrusive mafic sill at the studied locality. Sedimentary organic matter (kerogen) was investigated along two vertical stratigraphic transects to determine the spatial variability of its geochemical preservation. Thermal alteration of the preserved kerogen (as measured by Raman spectroscopy) increased toward the mafic sill, but the alteration was greater for kerogen preserved in carbonate mineralogies compared to that preserved in quartz (chert). Bulk δ13Corg values fluctuate throughout each vertical section, with a total average of −28.2‰ ± 0.8‰; however, values are unexpectedly lower for samples near the mafic sill, approaching −30‰, inconsistent with previously reported patterns. These measurements indicate that thermal alteration of sedimentary rocks does not universally result in 13C enrichment and increased δ13Corg values and suggests that ancient kerogen may be preferentially shielded from postdepositional heating effects due to micrometre-scale differences in mineralogy.
High-pressure structural phase transitions, electronic properties, and intermediate states of CaSe
Authors: Kürkçü Cihan
Published: March 2019

In this study, ab initio calculations have been carried out to understand the effect of extreme external pressure on the crystal structure of CaSe. The crystal structure of CaSe, a calcium chalcogen, is studied using density functional theory (DFT) with the generalized gradient approximation (GGA) up to 250 GPa under high hydrostatic pressure. Structurally CaSe crystallizes in cubic NaCl-type (B1) structure (space group: [Formula: see text]) at ambient conditions. The results indicated that CaSe undergoes a structural phase transition from this cubic structure to another cubic CsCl-type (B2) structure (space group: [Formula: see text]) at high pressure. This transformation is based on two intermediate states with space group [Formula: see text] and C2/m. Additionally, the electronic band structures and density of states for the obtained B1 and B2 structures of CaSe have been calculated. According to these calculations, obtained band gap values are in good agreement with the values reported in the literature.
Effect of febuxostat on biochemical parameters of hyperlipidemia induced by a high-fat diet in rabbits
Authors: Heikal Mohammed M. , Shaaban Ahmed A. , Elkashef Wagdi F. , Ibrahim Tarek M.
Published: March 2019

Febuxostat, a highly potent xanthine oxidase inhibitor with an antioxidant effect, inhibits elevated xanthine oxidase, leading to reduction of reactive oxygen species and oxidative stress, the main causes of vascular inflammation in hyperlipidemia. The aim of this study was to test the potential antioxidant and anti-inflammatory effects of febuxostat and (or) stopping a high-fat diet on the biochemical parameters in rabbits with hyperlipidemia induced by a high-fat diet. Male New Zealand rabbits were distributed into 3 groups: a normal control group fed standard chow for 12 weeks and 2 other groups fed a high-fat diet with 1% cholesterol for 8 weeks, and then shifted to standard chow for 4 weeks. During the last 4 weeks, one high-fat diet group received 0.5% carboxymethyl cellulose, whereas the other group was treated with febuxostat (2 mg/kg per day p.o.). Febuxostat significantly lowered low-density lipoprotein cholesterol (“bad” cholesterol) compared to the untreated group (high-fat diet group). Febuxostat also displayed a potent anti-inflammatory and antioxidant activity by decreasing serum levels of lipid peroxidation index, proinflammatory cytokines, and enhancing antioxidant enzyme activity. Stopping the hyperlipidemic diet in the high-fat diet group did not show improvement. These findings indicate the antioxidant and anti-inflammatory effects of febuxostat that may be common mechanisms of the anti-hyperlipidemic effect of this drug. Stopping a hyperlipidemic diet without treatment is not sufficient once injury has occurred.
Optimization of high-speed turning parameters for Inconel 713C based on Taguchi grey relational analysis
Authors: Parthiban V. , Vijayakumar S. , Sakthivel M.
Published: March 2019

In this work, a propelled dynamic approach, Taguchi grey relational analysis has been employed to estimate the impact of untreated and cryogenically treated and oil-quenched WC-Co tools in high-speed turning of Inconel 713C alloy on cutting force and surface roughness. Taguchi grey relational analysis is executed to maximize the high-speed turning of Inconel 713C alloy taking into account various operating parameters (cutting speed, feed rate, and depth of cut). The L27 orthogonal array has been utilized to determine the signal-to-noise ratio. Analysis of variance was performed to recognize the large number of components influencing surface roughness. The numerical examination showed that feed rate, with percentages as high as 95%, had the most predominant impact on machining performance, followed by cutting speed for untreated and treated WC-Co tools.
Topological full groups of ample groupoids with applications to graph algebras
Authors: Nyland Petter , Ortega Eduard
Published: March 2019

We study the topological full group of ample groupoids over locally compact spaces. We extend Matui’s definition of the topological full group from the compact to the locally compact case. We provide two general classes of étale groupoids for which the topological full group, as an abstract group, is a complete isomorphism invariant, hereby extending Matui’s Isomorphism Theorem. As an application, we study graph groupoids and their topological full groups, and obtain sharper results for this class. The machinery developed in this process is used to prove an embedding theorem for ample groupoids, akin to Kirchberg’s Embedding Theorem for [Formula: see text]-algebras. Consequences for graph [Formula: see text]-algebras and Leavitt path algebras are also spelled out. In particular, we improve on a recent embedding theorem of Brownlowe and Sørensen for Leavitt path algebras.
The generalized uncertainty principle from the doubly special relativity: Algebraic approach, Ramsauer effect and delta potential
Authors: Chung Won Sang , Hassanabadi Hassan , Kang Min Su , Sung Hee Hun , Maeng Jinyeob , Lee Seunghyun , Moon Young Il
Published: March 2019

In this paper, we consider the DSR-GUP which was first proposed by two of us [W. S. Chung and H. Hassanabadi, Phys. Lett. B 785, 127 (2018)]. Here, we introduce the deformed derivative corresponding to DSR-GUP to discuss the quantum mechanics based on DSR-GUP in an algebraical way. We use the deformed Fourier transform and its inverse transform to discuss the plane wave in [Formula: see text]-space and Gaussian packet. We also extend our discussion to the (1 + 1)-dimensional case. As examples, we discuss the Ramsauer–Townsend effect and delta potential.
Noncommutative coupled complex modified Korteweg–de Vries equation: Darboux and binary Darboux transformations
Authors: Riaz H. Wajahat A.
Published: March 2019

Higher-order nonlinear evolution equations are important for describing the wave propagation of second- and higher-order number of fields in optical fiber systems with higher-order effects. One of these equations is the coupled complex modified Korteweg–de Vries (ccmKdV) equation. In this paper, we study noncommutative (nc) generalization of ccmKdV equation. We present Darboux and binary Darboux transformations (DTs) for the nc-ccmKdV equation and then construct its Quasi-Grammian solutions. Further, single and double-hump soliton solutions of first- and second-order are given in commutative settings.
Non-flat FRW universe version of Tsallis holographic dark energy in specific modified gravity
Authors: Jawad Abdul , Rani Shamaila , Azhar Nadeem
Published: March 2019

Among various dark energy models, Tsallis holographic dark energy model shows the dynamical enthusiasm to describe the transition phase of the universe. In this paper, we consider Tsallis holographic dark energy with event and apparent horizon as an infrared cutoff in the framework of dynamical Chern–Simon modified gravity and non-flat FRW universe. We explore Hubble, equation of state and deceleration parameters and found that Hubble parameter lies in the range [Formula: see text] and [Formula: see text] for event and apparent horizon trajectories, respectively. It is mentioned here that the equation of state parameter lies within the range [Formula: see text] (event) and [Formula: see text] (apparent). Also, deceleration parameter for both cases show accelerated and decelerated phase of universe as well as cosmological constant. Moreover, we also checked the stability of our model through square speed of sound, which shows the positive behavior (exhibits the stability of the model). Finally, we observe that the generalized second law of thermodynamics remains valid in both cases of horizon.
Acoustic radiation simulation and pre-stress effect on compact acoustic levitation platform
Authors: Wei Bin , He Yongyong , Wang Wei
Published: March 2019

In order to satisfy the requirements of precise components with tidiness, low power and high stability in the field of biological engineering, medical equipment and semiconductors etc. a pre-stress acoustic transport prototype without horn was proposed in this paper. The mechanism of levitation and transport which is driven by orthogonal waves was revealed by the analysis of waveform and squeeze film characteristics in high-frequency exciting condition; also, the electric, solid and acoustic coupled finite element method (FEM) was established to investigate the effect of pre-stress and acoustic pressure distribution in the near field. The levitation and driving capacity of near field acoustic levitation (NFAL) transport platform without horns can be proved in this experiment and further to achieve the goal of parameters optimization. The theoretical and experimental results indicate that the pre-stress has a significant effect on resonant frequency and levitating stability, the pre-stress are determined by the DC voltage offset which is related to the system working point so that we cannot increase the offset and exciting voltage unlimitedly to improve the stability. At the same time, the calculated pressure distribution of acoustic radiation can generally reflect the regional bearing capacity in near and far field for levitation. These achievements can partly solve the problem of accuracy design of prototype and thickness of gas film, supporting for accuracy close loop control of levitating height.
Machine Learning Techniques for Code Smells Detection: A Systematic Mapping Study
Authors: Caram Frederico Luiz , Rodrigues Bruno Rafael De Oliveira , Campanelli Amadeu Silveira , Parreiras Fernando Silva
Published: March 2019

Code smells or bad smells are an accepted approach to identify design flaws in the source code. Although it has been explored by researchers, the interpretation of programmers is rather subjective. One way to deal with this subjectivity is to use machine learning techniques. This paper provides the reader with an overview of machine learning techniques and code smells found in the literature, aiming at determining which methods and practices are used when applying machine learning for code smells identification and which machine learning techniques have been used for code smells identification. A mapping study was used to identify the techniques used for each smell. We found that the Bloaters was the main kind of smell studied, addressed by 35% of the papers. The most commonly used technique was Genetic Algorithms (GA), used by 22.22% of the papers. Regarding the smells addressed by each technique, there was a high level of redundancy, in a way that the smells are covered by a wide range of algorithms. Nevertheless, Feature Envy stood out, being targeted by 63% of the techniques. When it comes to performance, the best average was provided by Decision Tree, followed by Random Forest, Semi-supervised and Support Vector Machine Classifier techniques. 5 out of the 25 analyzed smells were not handled by any machine learning techniques. Most of them focus on several code smells and in general there is no outperforming technique, except for a few specific smells. We also found a lack of comparable results due to the heterogeneity of the data sources and of the provided results. We recommend the pursuit of further empirical studies to assess the performance of these techniques in a standardized dataset to improve the comparison reliability and replicability.
Infinitely many solutions for critical quasilinear equations involving Hardy potential
Authors: Gao Fengshuang , Guo Yuxia
Published: March 2019

In this paper, we consider the following quasilinear elliptic equation with critical growth and a Hardy term: [Formula: see text]

where [Formula: see text], [Formula: see text] is a constant, [Formula: see text][Formula: see text] is the Sobolev critical exponent. And [Formula: see text] is an open bounded domain which contains the origin. We will study the existence of infinitely many solutions for (P). To achieve this goal, we first perform various kinds of change of variables to overcome the difficulties caused by the unboundedness of [Formula: see text] ([Formula: see text] for large [Formula: see text]) and the lack of a global monotone condition [Formula: see text] (see below) on [Formula: see text], then combining the idea of regularization approach and subcritical approximation we prove the existence of infinitely many solutions for (P). Our results show that under some suitable assumptions on [Formula: see text], without the perturbation of the lower term [Formula: see text] we can still obtain the existence of infinitely many solutions for (P).
Choquard equations with critical nonlinearities
Authors: Li Xinfu , Ma Shiwang
Published: March 2019

In this paper, we study the Brezis–Nirenberg type problem for Choquard equations in [Formula: see text] [Formula: see text] where [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] or [Formula: see text] are the critical exponents in the sense of Hardy–Littlewood–Sobolev inequality and [Formula: see text] is the Riesz potential. Based on the results of the subcritical problems, and by using the subcritical approximation and the Pohožaev constraint method, we obtain a positive and radially nonincreasing ground-state solution in [Formula: see text] for the problem. To the end, the regularity and the Pohožaev identity of solutions to a general Choquard equation are obtained.
Homogenization and correctors for linear stochastic equations via the periodic unfolding methods
Authors: Mohammed Mogtaba
Published: March 2019

In this paper, we use the periodic unfolding method and Prokhorov’s and Skorokhod’s probabilistic compactness results to obtain homogenization and corrector results for stochastic partial differential equations (PDEs) with periodically oscillating coefficients. We show the convergence of the solutions of the original problems to the solutions of the homogenized problems. In contrast to the two-scale convergence method, the corrector results obtained in this paper are without any additional regularity assumptions on the solutions of the original problems
Analysis and Optimization of Surface Roughness and Microhardness for Roller Burnishing using Response Surface Methodology and Desirability Function Approach on Aluminum 63400
Authors: Kurkute Vijay , Chavan Sandip
Published: March 2019

In the present study, response surface methodology (RSM) has been used to optimize roller burnishing process for aluminum alloy 63400 grade. Single roller burnishing tool (carbide) is used to burnish round aluminum alloy. Experiments were performed with Box and Wilson Central Composite Design (CCD). The machining factors controlled during experimentation are speed, feed, force and number of tool passes. The response parameters are surface roughness and microhardness. The most significant control factors on the surface roughness and microhardness were determined by analysis of variance (ANOVA). A controllable process parameter is correlated with surface roughness and microhardness by mathematical model. A quadratic regression analysis is performed to compute the correlation coefficient between the experimental and predicted values. The optimum surface roughness and microhardness foreseen by the model is found to agree well with the results of the experiment. To find the optimum value of both the response, desirability approach was used. The input parameters with most desirability value are selected as the optimum solution. Hence, the most desirable burnished condition desirability value 0.872 is speed 37.9[Formula: see text]m/min, feed 0.5[Formula: see text]mm/rev, force 35.49[Formula: see text]N and number of tool passes four. Surface roughness obtained is 0.524[Formula: see text][Formula: see text] m and microhardness is 125.02[Formula: see text]HV. This is the optimum condition for minimum surface roughness and maximum microhardness. The optimum surface finish and microhardness predicted by the model are found to agree well with the results of the experiment.
Novel Transparent Boundary Conditions for the Regularized Long Wave Equation
Authors: Abounouh M. , Al-Moatassime H. , Kaouri S.
Published: March 2019

In this paper, we present a new method to derive transparent boundary conditions for the Regularized Long Wave equation and its linearized equation. These boundary conditions have the advantage of being exact for both linearized and nonlinear equations. The resulting problems supplemented with initial data are approximated numerically using finite difference method in space discretization and Crank–Nicolson scheme in time for the linearized equation, while implicit scheme in time is used for the Regularized Long Wave equation. Numerical experiments are made for solitary initial data and various source terms to illustrate the transparency of the introduced boundary conditions. Results are compared with the use of usual boundary conditions, namely, Dirichlet and Neumann via infinite norm error on the boundary and also by displaying geophones and instantaneous figures.
Comparison of Medical Decision-Making with Intuitionistic Fuzzy Parametrized Fuzzy Soft Set and Riesz Summability
Authors: Kirişci Murat
Published: March 2019

In the present study, for the medical decision-making problem, the proposed techniques related to the intuitionistic fuzzy parametrized soft sets and Riesz mean methods were used. The results of the given methods were compared. The values obtained from the methods were ordered and the success of the measurement techniques of the methods were evaluated. The real dataset which is called Cleveland heart disease dataset was applied in this problem.
On a recent reciprocity formula for Dedekind sums
Authors: Girstmair Kurt
Published: March 2019

Let [Formula: see text] denote the classical Dedekind sum and [Formula: see text]. Recently, Du and Zhang proved the following reciprocity formula. If [Formula: see text] and [Formula: see text] are odd natural numbers, [Formula: see text], then [Formula: see text] where [Formula: see text] and [Formula: see text]. In this paper, we show that this formula is a special case of a series of similar reciprocity formulas. Whereas Du and Zhang worked with the connection of Dedekind sums and values of [Formula: see text]-series, our main tool is the three-term relation for Dedekind sums.
Experimental study on the effects of Kursi Ziyabet on the rat model of diabetes mellitus
Authors: Parhat Alimjan , Huojiaaihemaiti Haibaier , Mohammadturusn Nabijan , Nurahmat Mammat
Published: March 2019

Objective: To evaluate the hyperglycemic effects of Kursi Ziyabet (KZ) tablets on the rat models of diabetes mellitus.

Methods: In total, 58 male SD rats were assigned randomly to six groups. All except the normal group were transformed into experimental diabetes mellitus rat models by injecting streptozocin. The hyperglycemic effect and the mechanism of Ziyabet were evaluated by body weight, food and water intake, fasting blood sugar, and related parameters by measuring the oxidative stress-related factors and lipid metabolism indicator level by the corresponding kits using the rat experimental models.

Results: Compared with the model group, body weight markedly increased after 3–6 weeks of intragastric administration of Ziyabet tablets ([Formula: see text]), while the water intake significantly decreased in the same period of time ([Formula: see text]). Food intake and fasting blood sugar level also decreased with the high dosage of Ziyabet tablets ([Formula: see text]). There is no significant difference in pancreas’ MDA content of the Ziyabet groups when compared to the model group ([Formula: see text]), while significant increase in SOD level was observed in high-dosage KZ group ([Formula: see text]). The blood serum insulin and free fatty acid level also decreased in the high-dosage KZ group compared with the model group ([Formula: see text]).

Conclusion: We conclude that Ziyabet tablets demonstrated protective effects on the diabetic rat models.
Zika Virus Infection and Implications for Reproduction
Authors: Giles Michelle L. , Cole Stephen
Published: March 2019

Zika virus infection during pregnancy can have devastating effects on the foetus leading to congenital Zika syndrome. It is relevant therefore for couples living in countries with endemic Zika virus to understand the strategies they can utilise to reduce the chance of infection. In addition, couples planning pregnancy, or who are already pregnant, travelling to countries with Zika virus need to be informed of the potential risk and implications for future reproductive planning.
A Fruitful Journey: Pollen Tube Navigation from Germination to Fertilization
Authors: Johnson Mark A. , Harper Jeffrey F. , Palanivelu Ravishankar
Published: March 2019

In flowering plants, pollen tubes undergo tip growth to deliver two nonmotile sperm to the ovule where they fuse with an egg and central cell to achieve double fertilization. This extended journey involves rapid growth and changes in gene activity that manage compatible interactions with at least seven different cell types. Nearly half of the genome is expressed in haploid pollen, which facilitates genetic analysis, even of essential genes. These unique attributes make pollen an ideal system with which to study plant cell–cell interactions, tip growth, cell migration, the modulation of cell wall integrity, and gene expression networks. We highlight the signaling systems required for pollen tube navigation and the potential roles of Ca2+ signals. The dynamics of pollen development make sexual reproduction highly sensitive to heat stress. Understanding this vulnerability may generate strategies to improve seed crop yields that are under threat from climate change.
Functional Status of Xylem Through Time
Authors: Brodersen Craig R. , Roddy Adam B. , Wason Jay W. , McElrone Andrew J.
Published: March 2019

Water transport in vascular plants represents a critical component of terrestrial water cycles and supplies the water needed for the exchange of CO2in the atmosphere for photosynthesis. Yet, many fundamental principles of water transport are difficult to assess given the scale and location of plant xylem. Here we review the mechanistic principles that underpin long-distance water transport in vascular plants, with a focus on woody species. We also discuss the recent development of noninvasive tools to study the functional status of xylem networks in planta. Limitations of current methods to detect drought-induced xylem blockages (e.g., embolisms) and quantify corresponding declines in sap flow, and the coordination of hydraulic dysfunction with other physiological processes are assessed. Future avenues of research focused on cross-validation of plant hydraulics methods are discussed, as well as a proposed fundamental shift in the theory and methodology used to characterize and measure plant water use.
Hydrogel-Based Strategies to Advance Therapies for Chronic Skin Wounds
Authors: da Silva Lucília P. , Reis Rui L. , Correlo Vitor M. , Marques Alexandra P.
Published: March 2019

Chronic skin wounds are the leading cause of nontraumatic foot amputations worldwide and present a significant risk of morbidity and mortality due to the lack of efficient therapies. The intrinsic characteristics of hydrogels allow them to benefit cutaneous healing essentially by supporting a moist environment. This property has long been explored in wound management to aid in autolytic debridement. However, chronic wounds require additional therapeutic features that can be provided by a combination of hydrogels with biochemical mediators or cells, promoting faster and better healing. We survey hydrogel-based approaches with potential to improve the healing of chronic wounds by reviewing their effects as observed in preclinical models. Topics covered include strategies to ablate infection and resolve inflammation, the delivery of bioactive agents to accelerate healing, and tissue engineering approaches for skin regeneration. The article concludes by considering the relevance of treating chronic skin wounds using hydrogel-based strategies.
Inorganic arsenic exposure induces sex-disparate effects and exacerbates ischemia-reperfusion injury in the female heart
Authors: Veenema Ryne , Casin Kevin M. , Sinha Prithvi , Kabir Raihan , Mackowski Nathan , Taube Nicole , Bedja Djahida , Chen Rui , Rule Ana , Kohr Mark J.
Published: March 2019

Arsenic is a common contaminant in drinking water throughout the world, and recent studies support a link between inorganic arsenic (iAS) exposure and ischemic heart disease in men and women. Female hearts exhibit an estrogen-dependent reduction in susceptibility to myocardial ischemic injury compared with males, and as such, female hearts may be more susceptible to the endocrine-disrupting effects of iAS exposure. However, iAS exposure and susceptibility to ischemic heart injury have not been examined in mechanistic studies. Male and female mice (8 wk) were exposed to environmentally relevant concentrations of sodium arsenite (0, 10, 100, and 1,000 parts/billion) via drinking water for 4 wk. Pre- and postexposure echocardiography was performed, and postexposure plasma was collected for 17β-estradiol measurement. Hearts were excised and subjected to ischemia-reperfusion (I/R) injury via Langendorff perfusion. Exposure to 1,000 parts/billion iAS led to sex-disparate effects, such that I/R injury was exacerbated in female hearts but unexpectedly attenuated in males. Assessment of echocardiographic parameters revealed statistically significant structural remodeling in iAS-treated female hearts with no change in function; males showed no change. Plasma 17β-estradiol levels were not significantly altered by iAS in male or female mice versus nontreated controls. Although total eNOS protein levels did not change in whole heart homogenates from iAS-treated male or female mice, eNOS phosphorylation (Ser1177) was significantly elevated in iAS-treated male hearts. These results suggest that iAS exposure can induce sex-disparate effects and modulate susceptibility to ischemic heart injury by targeting distinct sex-dependent pathways.

NEW & NOTEWORTHY This is the first mechanistic study examining iAS exposure on myocardial ischemia-reperfusion injury in male and female mice. Following iAS exposure, ischemia-reperfusion injury was exacerbated in female hearts but attenuated in males. iAS treatment induced statistically significant cardiac remodeling in females, with no change in males. iAS treatment also enhanced phosphorylated eNOS levels at Ser1177, but only in male hearts. These results suggest that iAS alters susceptibility to myocardial I/R injury through distinct sex-dependent pathways.
Angiotensin II type 2 receptor stimulation with compound 21 improves neurological function after stroke in female rats: a pilot study
Authors: Eldahshan Wael , Ishrat Tauheed , Pillai Bindu , Sayed Mohammed A. , Alwhaibi Abdulrahman , Fouda Abdelrahman Y. , Ergul Adviye , Fagan Susan C.
Published: March 2019

The angiotensin II type 2 receptor (AT2R) agonist, compound 21 (C21), has been shown to be neurovascularly protective after ischemic stroke in male rats. In the current study, we aim to study the impact of C21 treatment on female rats. Young female Wistar rats were subjected to different durations of middle cerebral artery occlusion (MCAO) (3 h, 2 h, and 1 h) using a silicone-coated monofilament, treated at reperfusion with 0.03 mg/kg ip of C21 and followed up for different times (1, 3, and 14 days) after stroke. Behavioral tests were performed (Bederson, paw grasp, beam walk, and rotarod), and animals were euthanized for infarct size analysis and Western blot analysis. In vitro, primary male and female brain microvascular endothelial cells (ECs) were grown in culture, and the expression of the AT2R was compared between males and females. At 1 day, C21 treatment resulted in an improvement in Bederson scores. However, at 3 days and 14 days, the impact of C21 on stroke outcomes was less robust. In vitro, the expression of the AT2R was significantly higher in female ECs compared with male ECs. In conclusion, C21 improves Bederson scores after stroke in female rats when administered early at reperfusion. The ability of C21 to exert its neuroprotective effects might be affected by fluctuating levels of female hormones.

NEW & NOTEWORTHY The present study shows the neuroprotective impact of C21 on ischemic stroke in female rats and how the protective effects of C21 can be influenced by the hormonal status of female rodents.
Muscle metaboreflex-induced central blood volume mobilization in heart failure
Authors: O’Leary Donal S. , Senador Danielle , Augustyniak Robert A.
Published: March 2019

Underperfusion of active skeletal muscle causes metabolites to accumulate and stimulate group III and IV skeletal muscle afferents, which triggers a powerful pressor response termed the muscle metaboreflex. Muscle metaboreflex activation (MMA) during submaximal dynamic exercise in healthy individuals increases arterial pressure mainly via substantial increases in cardiac output (CO). The increases in CO occur via the combination of tachycardia and increased ventricular contractility. Importantly, MMA also elicits substantial central blood volume mobilization, which allows the ventricular responses to sustain the increases in CO. Otherwise preload would fall and the increases in CO could not be maintained. In subjects with systolic heart failure (HF), the ability to increase CO during exercise and MMA is markedly reduced, which has been attributed to impaired ventricular contractility. Whether the ability to maintain preload during MMA in HF is preserved is unknown. Using a conscious chronically instrumented canine model, we observed that MMA in HF is able to raise central blood volume similarly as in normal subjects. Therefore, the loss of the ability to raise CO during MMA in HF is not because of the loss of the ability to mobilize blood volume centrally.

NEW & NOTEWORTHY In normal subjects during dynamic exercise muscle metaboreflex activation elicits large increases in cardiac output that occur via increases in heart rate, ventricular contractility, and, importantly, marked central blood volume mobilization that acts to maintain ventricular preload, thereby allowing the changes in cardiac function to maintain the increases in cardiac output. In subjects with heart failure, the ability to raise cardiac output during muscle metaboreflex activation is impaired. We investigated whether this is because of the inability to maintain ventricular preload. We found that this reflex is still able to elicit large increases in central blood volume, and therefore the limited ability to raise cardiac output likely stems from ventricular dysfunction and not the ability to maintain preload.
The Blocking Mechanism of the Vertical Feeding System of Roadside Support Body Material for Backfilling Gob‐Side Entry Retaining
Authors: Gong Peng , Ma Zhanguo , Sun Jian , Zhang Ray Ruichong
Published: March 2019

Reliable operation of the feeding system plays a crucial role in ensuring the safe and efficient production of the working face of backfilling gob‐side entry retaining (GER). In the process of vertical feeding of the roadside support body material, the problem of blocking of the feeding shaft has occurred to the test mine, which seriously affects the production safety in mines. In this paper, based on the theoretical analysis, a fluid‐solid coupling numerical model was established. The change rules of the speed of sacked gangue, pressure of air below it, and speed vector distribution with different vent diameters were obtained. The blocking mechanism of the feeding system was revealed. The results show that if the exhaust vent of the stock bin was shut, the speed of gangue in the mine increased and then decreased and finally blocked in the feeding shaft. If the exhaust vent of the stock bin was opened for pressure discharge, with the increase of diameter of the exhaust vent, the maximum speed and ending speed of sacked gangue increased, pressure differential reduced, and speed vector was uniformly distributed. The energy criterion of blocking of the feeding shaft was further obtained. Based on the engineering conditions of the test mine, when the feeding shaft is blocked, the critical value of diameter of the exhaust vent is 30 mm. The research results provide basis for the design of key parameters of the vertical feeding system, ensuring the safe and efficient production of gob‐backfilled GER working face.
The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect
Authors: ten Broeke Sanne W. , Rodríguez-Girondo Mar , Suerink Manon , Aretz Stefan , Bernstein Inge , Capellá Gabriel , Engel Christoph , Gomez-Garcia Encarna B. , van Hest Liselot P. , von Knebel Doeberitz Magnus , Lagerstedt-Robinson Kristina , Letteboer Tom G.W. , Moller Pal , van Os Theo A. , Pineda Marta , Rahner Nils , Olderode-Berends Maran J.W. , von Salomé Jenny , Schackert Hans K. , Spruijt Liesbeth , Steinke-Lange Verena , Wagner Anja , Tops Carli M.J. , Nielsen Maartje
Published: March 2019

Background:

PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families.

Methods:

The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias.

Results:

Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162–4.328] for the second generation and 2.644 (95% CI, 1.082–6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648–2.619) and HR = 1.074 (95% CI, 0.406–2.842) for second and third generations, respectively].

Conclusions:

Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome.

Impact:

This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition.
Immunotherapy in Non–Small Cell Lung Cancer: Facts and Hopes
Authors: Doroshow Deborah B. , Sanmamed Miguel F. , Hastings Katherine , Politi Katerina , Rimm David L. , Chen Lieping , Melero Ignacio , Schalper Kurt A. , Herbst Roy S.
Published: March 2019

Immune-checkpoint inhibitors (ICI), particularly inhibitors of the PD-1 axis, have altered the management of non–small cell lung cancer (NSCLC) over the last 10 years. First demonstrated to improve outcomes in second-line or later therapy of advanced disease, ICIs were shown to improve overall survival compared with chemotherapy in first-line therapy for patients whose tumors express PD-L1 on at least 50% of cells. More recently, combining ICIs with chemotherapy has been shown to improve survival in patients with both squamous and nonsquamous NSCLC, regardless of PD-L1 expression. However, PD-L1 and, more recently, tumor mutational burden have not proven to be straightforward indicative biomarkers. We describe the advances to date in utilizing these biomarkers, as well as novel markers of tumor inflammation, to ascertain which patients are most likely to benefit from ICIs. Ongoing translational work promises to improve the proportion of patients who benefit from these agents.
Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth
Authors: Lamano Jonathan B. , Lamano Jason Balquidera , Li Yuping D. , DiDomenico Joseph D. , Choy Winward , Veliceasa Dorina , Oyon Daniel E. , Fakurnejad Shayan , Ampie Leonel , Kesavabhotla Kartik , Kaur Rajwant , Kaur Gurvinder , Biyashev Dauren , Unruh Dusten J. , Horbinski Craig M. , James C. David , Parsa Andrew T. , Bloch Orin
Published: March 2019

Purpose:

Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation.

Experimental Design:

Conditioned media from patient-derived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate naïve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors.

Results:

GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8+ T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy.

Conclusions:

Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM.
Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis
Authors: Karginova Olga , Weekley Claire M. , Raoul Akila , Alsayed Alhareth , Wu Tong , Lee Steve Seung-Young , He Chuan , Olopade Olufunmilayo I.
Published: March 2019

Treatment of advanced breast cancer remains challenging. Copper and some of the copper-dependent proteins are emerging therapeutic targets because they are essential for cell proliferation and survival, and have been shown to stimulate angiogenesis and metastasis. Here, we show that DCAC50, a recently developed small-molecule inhibitor of the intracellular copper chaperones, ATOX1 and CCS, reduces cell proliferation and elevates oxidative stress, triggering apoptosis in a panel of triple-negative breast cancer (TNBC) cells. Inhibition of ATOX1 activity with DCAC50 disrupts copper homeostasis, leading to increased copper levels, altered spatial copper redistribution, and accumulation of ATP7B to the cellular perinuclear region. The extent and impact of this disruption to copper homeostasis vary across cell lines and correlate with cellular baseline copper and glutathione levels. Ultimately, treatment with DCAC50 attenuates tumor growth and suppresses angiogenesis in a xenograft mouse model, and prevents endothelial cell network formation in vitro. Co-treatment with paclitaxel and DCAC50 enhances cytotoxicity in TNBC and results in favorable dose reduction of both drugs. These data demonstrate that inhibition of intracellular copper transport targets tumor cells and the tumor microenvironment, and is a promising approach to treat breast cancer.
Mouse Strains Influence Clearance and Efficacy of Antibody and Antibody–Drug Conjugate Via Fc–FcγR Interaction
Authors: Li Fu , Ulrich Michelle L. , Shih Vincent Feng-Sheng , Cochran Julia H. , Hunter Joshua H. , Westendorf Lori , Neale Jason , Benjamin Dennis R.
Published: March 2019

To provide a better understanding of the pharmacokinetics–pharmacodynamics relationships of antibody-based drugs, we analyzed several chimeric and humanized monoclonal antibodies or antibody–drug conjugates (ADC) for PK and efficacy among four strains of mice. Notably, antibodies and ADCs displayed a dose-dependent drug disposition profile in the plasma of NSG mice. The increased clearance rate in NSG mice resulted in the reduction of antitumor activity of ADCs. Furthermore, we identified that the abnormal clearance was mediated by Fc–FcγR interaction by comparing antibodies that lack FcγR binding capacity. We also found a high percentage of FcγR-expressing macrophages in the bone marrow, spleen, and liver of NSG mice, which may be responsible for the abnormal distribution of antibodies. Overall, these findings suggest that preclinical evaluation of efficacy and pharmacokinetics of antibodies and ADCs need to consider mouse strain-induced variations.
HDAC3 Inhibition Upregulates PD-L1 Expression in B-Cell Lymphomas and Augments the Efficacy of Anti–PD-L1 Therapy
Authors: Deng Siyu , Hu Qianwen , Zhang Heng , Yang Fang , Peng Cheng , Huang Chuanxin
Published: March 2019

Programmed cell-death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway blockade is a promising therapy for the treatment of advanced cancers, including B-cell lymphoma. The clinical response to PD-1/PD-L1 immunotherapy correlates with PD-L1 levels on tumor cells and other cells in the tumor microenvironment. Hence, it is important to understand the molecular mechanisms that regulate PD-L1 expression. Here, we report that histone deacetylase 3 (HDAC3) is a crucial repressor of PD-L1 transcription in B-cell lymphoma. Pan-HDACs or selective HDAC3 inhibitors could rapidly increase histone acetylation and recruitment of bromodomain protein BRD4 at the promoter region of PD-L1 gene, leading to activation of its transcription. Mechanically, HDAC3 and its putative associated corepressor SMRT were recruited to the PD-L1 promoter by the transcriptional repressor BCL6. In addition, HDAC3 inhibition reduced DNA methyltransferase 1 protein levels to indirectly activate PD-L1 transcription. Finally, HDAC3 inhibition increased PD-L1 expression on dendritic cells in the tumor microenvironment. Combining selective HDAC3 inhibitor with anti–PD-L1 immunotherapy enhanced tumor regression in syngeneic murine lymphoma model. Our findings identify HDAC3 as an important epigenetic regulator of PD-L1 expression and implicate combination of HDAC3 inhibition with PD-1/PD-L1 blockade in the treatment of B-cell lymphomas.
What CAR Will Win the CD19 Race?
Authors: Quintás-Cardama Alfonso
Published: March 2019

Adoptive transfer of T cells engineered with synthetic receptors is emerging as a new pillar in the treatment of cancer. The adoptive cell therapy furthest along in clinical development is the engineering of T cells to express chimeric antigen receptors (CAR) against the CD19 antigen. Several platforms have shown remarkable activity in patients with relapsed or refractory B-cell malignancies. In 2017, the FDA approved the first CAR T cell products tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Gilead), and others are expected to follow shortly. Despite their activity, CAR T cell approaches have limitations that will need to be addressed, including excessive toxicity, relapses mediated via antigen escape, difficulties overcoming the suppressive tumor microenvironment, high manufacturing costs and retail prices, and patient access, among others. The CAR T cell product that better addresses those challenges will obtain a critical competitive advantage.
Antibody–Cytokine Fusions: Versatile Products for the Modulation of Anticancer Immunity
Authors: Neri Dario
Published: March 2019

The remarkable clinical success of immune-checkpoint inhibitors for the treatment of a growing number of cancer types has sparked interest in the discovery of novel forms of immunotherapy, which may be used alone or in combination. In this context, cytokine-based therapeutics are well poised to play a role in modern cancer therapy. This article focuses on antibody–cytokine fusion proteins (also called “immunocytokines”) as one class of biopharmaceuticals that can substantially improve the therapeutic index and, thus, the applicability of cytokine products. In many preclinical settings, antibodies can be used to preferentially deliver many (but not all) types of cytokines to primary and metastatic tumor lesions. The antibody-based delivery of certain proinflammatory payloads (such as IL2, IL12, and TNF) to the tumor microenvironment can lead to a dramatic potentiation of their anticancer activity. However, although some fusion proteins have advanced to late-stage clinical trials, much work remains to be done in order to fully characterize the mechanism of action and the pharmaceutical potential of immunocytokines in the clinical setting. Various factors contribute to in vivo performance, including the target antigen, the antibody properties, the nature of the payload, the format of the fusion protein, the dose, and schedule, as well as their use in combination with other therapeutic modalities. Protein engineering opportunities and insights in cancer immunology are contributing to the development of next-generation immunocytokine products and of novel therapeutic concepts, with the goal to increase antitumor activity and reduce systemic toxicity (a common problem for cytokine-based biopharmaceuticals).