bluuebunny/crossref_metadata_2025 huggingface dataset:
A comprehensive performance evaluation of the BinLPT workload‐aware loop scheduler
Authors: Penna Pedro Henrique , A. Gomes Antônio Tadeu , Castro Márcio , D.M. Plentz Patricia , C. Freitas Henrique , Broquedis François , Méhaut Jean‐François
Published: February 2019

Workload‐aware loop schedulers were introduced to deliver better performance than classical loop scheduling strategies. However, they presented limitations such as inflexible built‐in workload estimators and suboptimal chunk scheduling. Targeting these challenges, we proposed previously a workload‐aware scheduling strategy called BinLPT, which relies on three features: (i) user‐supplied estimations of the workload of the loop; (ii) a greedy heuristic that adaptively partitions the iteration space in several chunks; and (iii) a scheduling scheme based on the Longest Processing Time (LPT) rule and on‐demand technique. In this paper, we present two new contributions to the state‐of‐the‐art. First, we introduce a multiloop support feature to BinLPT, which enables the reuse of estimations across loops. Based on this feature, we integrated BinLPT into a real‐world elastodynamics application, and we evaluated it running on a supercomputer. Second, we present an evaluation of BinLPT using simulations as well as synthetic and application kernels. We carried out this analysis on a large‐scale NUMA machine under a variety of workloads. Our results revealed that BinLPT is better at balancing the workloads of the loop iterations and this behavior improves as the algorithmic complexity of the loop increases. Overall, BinLPT delivers up to 37.15% and 9.11% better performance than well‐known loop scheduling strategies, for the application kernels and the elastodynamics simulation, respectively.
Key node selection based on a genetic algorithm for fast patching in social networks
Authors: Kim Bongjae , Jung Jinman , Heo Junyoung , Min Hong
Published: February 2019

Online social network users provide considerable amounts of personal information and share this information with friends without space‐time limitations. The tight connectivity among users of social networks causes the rapid spreading of information. Given the popularity of social networking sites, there is a high probability of attacks. Worms target popular users with interesting information to infect them, as their higher reputations have more power in social networks. Therefore, timely patch propagation schemes must be able to inhibit the activity of worms. To improve the patch propagation speed, it is important to select key nodes that are the starting points of the patch process. In this paper, we proposed a key node selection scheme based on a genetic algorithm to find the most significant contribution nodes of patch propagation. We modeled the usage patterns of an online social network user and simulated the proposed scheme with data from this user. Simulation results show that the proposed scheme propagates patches more rapidly than existing schemes.
Factors Affecting Tamoxifen Metabolism in Patients With Breast Cancer: Preliminary Results of the French PHACS Study
Authors: Puszkiel Alicja , Arellano Cécile , Vachoux Christelle , Evrard Alexandre , Le Morvan Valérie , Boyer Jean‐Christophe , Robert Jacques , Delmas Caroline , Dalenc Florence , Debled Marc , Venat‐Bouvet Laurence , Jacot William , Suc Etienne , Sillet‐Bach Isabelle , Filleron Thomas , Roché Henri , Chatelut Etienne , White‐Koning Melanie , Thomas Fabienne
Published: February 2019

In addition to the effect of cytochrome P450 (CYP) 2D6 genetic polymorphisms, the metabolism of tamoxifen may be impacted by other factors with possible consequences on therapeutic outcome (efficacy and toxicity). This analysis focused on the pharmacokinetic (PK)‐pharmacogenetic evaluation of tamoxifen in 730 patients with adjuvant breast cancer included in a prospective multicenter study. Plasma concentrations of tamoxifen and six major metabolites, the genotype for 63 single‐nucleotide polymorphisms, and comedications were obtained 6 months after treatment initiation. Plasma concentrations of endoxifen were significantly associated with CYP2D6 diplotype (P < 0.0001), CYP3A4*22 genotype (P = 0.0003), and concomitant intake of potent CYP2D6 inhibitors (P < 0.001). Comparison of endoxifen levels showed that the CYP2D6 phenotype classification could be improved by grouping intermediate metabolizer (IM)/IM and IM/poor metabolizer diplotype into IM phenotype for future use in tamoxifen therapy optimization. Finally, the multivariable regression analysis showed that formation of tamoxifen metabolites was independently impacted by CYP2D6 diplotype and CYP3A4*22, CYP2C19*2, and CYP2B6*6 genetic polymorphisms.
Are cultural values sufficient to improve stakeholder engagement human and labour rights issues?
Authors: Cubilla‐Montilla Mitzi , Nieto‐Librero Ana‐Belén , Galindo‐Villardón Ma Purificación , Vicente Galindo Ma Purificación , Garcia‐Sanchez Isabel‐María
Published: February 2019

The complexity of the business world and current business models has motivated an increasing number of companies to disclose corporate information through sustainability reports. This reporting and stakeholders engagement may bring shared value to business and society in general although working towards sustainable development goals. This work adopts a new analytical approach by determining the global reporting initiative indicators related to labour practices and decent work, human rights, society, and product responsibility that are reported less frequently by companies. The final objective is to predict the influence that society's cultural values will play as a normative institutional pressure in their evolution. The results obtained for a sample comprising the 201 largest international companies that report in accordance with the recommendations of the G4 Guide in 2015 indicate that more than 50% of these large companies do not report specific mechanisms implemented to avoid violations of human rights and labour rights, or information on incidents related to production and commercial relations. Regulatory pressures associated with cultural values have limited effectiveness as drivers of greater corporate transparency in this area, as they are able to predict a favourable evolution for only 40% of companies that currently do not report.
Iron‐Catalyzed ortho C−H Arylation and Methylation of Pivalophenone N−H Imines
Authors: Xu Wengang , Yoshikai Naohiko
Published: February 2019

Iron‐catalyzed ortho C−H arylation and methylation reactions of pivalophenone N−H imines are reported. The pivaloyl N−H imine proved an excellent directing group for the arylation with diarylzinc reagents in the presence of an iron‐diphosphine catalyst and 2,3‐dichlorobutane at room temperature. A similar catalytic system also allowed methylation with Me3Al at 70 °C. The pivaloyl imine of the product could be readily converted to a cyano group, thus allowing convenient preparation of ortho‐functionalized benzonitriles.
Memcapacitor emulator based on the Miller effect
Authors: Romero Francisco J. , Morales Diego P. , Godoy Andres , Ruiz Francisco G. , Tienda‐Luna Isabel M. , Ohata Akiko , Rodriguez Noel
Published: February 2019

This work provides the guidelines to design and implement an elemental memcapacitor circuit emulator based on the relation between memcapacitance and the Miller effect in voltage amplifiers. The emulator is presented theoretically in a top‐down approach, from the circuit behavior to the foundations of the constitutive equations of the memcapacitance and the electrical mutation of a memristor. Then, a practical and simple circuit implementation is demonstrated by SPICE computer simulations, circumventing the solid‐state memristor by a two‐state flux‐dependent resistor, which modulates the gain of the amplifier in consonance to the flux of the input signal. Further electrical properties of the system are extracted from its physical implementation in a field‐programmable analog array. The work is concluded illustrating the functionality of the memcapacitor emulator to study neuromorphic applications with a long‐term potentiation example.
Dynamic switch migration with noncooperative game towards control plane scalability in SDN
Authors: Wu Guowei , Wang Jinlei , Obaidat Mohammad S. , Yao Lin , Hsiao Kuei‐Fang
Published: February 2019

As software‐defined networking (SDN) is a logically centralized technology, the control plane scalability in SDN is increasingly important with the network scale increasing. Load balancing and maximizing resource utilization are very critical to the control plane in SDN, while switch migration is an effective approach to achieve these two performance metrics. However, switch migration is NP‐hard problem because it belongs to the problem of combinatorial optimization. To avoid the NP‐hard problem, we propose a switch migration scheme by adopting noncooperative game to improve the control plane scalability in SDN. First, we design a novel load balancing monitoring scheme to detect the load imbalance between controllers and trigger migrating switches. Then, we use noncooperative game among controllers to decide switch migration to get the maximizing overall profits. Last, we prove that our proposed approach can get Pareto optimality. Extensive simulations prove that our method is able to achieve a more scalable control plane with load balancing and maximizing resource utilization.
In a squeeze: Epibiosis may affect the distribution of kelp forests
Authors: Sogn Andersen Guri , Moy Frithjof E. , Christie Hartvig
Published: February 2019

The processes limiting the population recovery of the kelp Saccharina latissima after recent large‐scale loss from the south coast of Norway are poorly understood. Previous investigations do, however, suggest that the impacts of biotic interactions (epibiosis and competition) and increased water turbidity are important. We investigated the depth‐related patterns of growth, epibiosis, and mortality in two sample populations of kelp, from the south and the southwest coast of Norway. The investigations were performed over a period of seven months, in a crossed translocational study, where kelps were mounted on rigs at six depths (1, 3, 6, 9, 15, and 24 m). In a second experiment, the amounts of light blocked by different epibiont layers growing on the kelp frond were investigated. While growth decreased with depth in spring and summer, the kelp grew faster at 15 m than at shallower depths in fall. Survival was low both in shallow water and below 15 m depth. Epibionts covered the kelp growing at depths from 1 to 9 m, and the laboratory study showed that the coverage may have deprived the individuals of as much as 90% of the available light. Although the depth‐related results we present apply—in the strictest sense—only to kelp translocated on rigs, we argue that the relative patterns are relevant for natural populations. Growth and survival of S. latissima is likely to be reduced by heavy loads of epibionts, while depths where epibionts are sparse may be close to the lower limit of the kelps depth distribution along the south coast of Norway. This suggests that a vertical squeeze, or narrowing of the distribution range of kelp forests may be occurring in Norway.
Coastal marine ecosystem connectivity: pelagic ocean to kelp forest subsidies
Authors: Zuercher Rachel , Galloway Aaron W. E.
Published: February 2019

The movement of trophic resources between and among ecosystems, referred to as cross‐ecosystem subsidies, is a common phenomenon. In the marine environment, both adjacent and distant ecosystems are connected by oceanographic forces that transport nutrients, organisms, and other materials. Kelp forest ecosystems are one example of an open marine system that both exports and receives trophic subsidies. Though rocky reefs are rich in kelp‐based energy produced internally, kelp forest organisms also rely on phytoplankton, and the influx of holoplankton and meroplankton from adjacent open ocean habitats. In this paper, we seek to clarify the identity of holoplanktonic and meroplanktonic subsidies, quantify their energetic and nutrient contributions to the kelp forest, and further explore the impacts of these subsidies for individual consumers and for kelp forest communities. We reviewed six individual subsidy organisms that are commonly advected to kelp forests on the West coast of North America, and show that these organisms from the pelagic ocean represent important resource pulses for kelp forest consumers. In addition, we summarize the characteristics of subsidies, consumers, and recipient ecosystems that provide insight into the dynamics of subsidy influx and impacts to recipient systems. Finally, we provide suggestions as scientists move forward with efforts to quantify the impacts of cross‐ecosystem subsidies. Trophic subsidies are a major force shaping both marine and terrestrial communities and ecosystems. Quantitative information about these subsidies and their impacts on food webs will not only improve our understanding of these ecosystems, but also improve food web models, and predictions of ecosystem response to change.
Tree mortality submodels drive simulated long‐term forest dynamics: assessing 15 models from the stand to global scale
Authors: Bugmann Harald , Seidl Rupert , Hartig Florian , Bohn Friedrich , Brůna Josef , Cailleret Maxime , François Louis , Heinke Jens , Henrot Alexandra‐Jane , Hickler Thomas , Hülsmann Lisa , Huth Andreas , Jacquemin Ingrid , Kollas Chris , Lasch‐Born Petra , Lexer Manfred J. , Merganič Ján , Merganičová Katarína , Mette Tobias , Miranda Brian R. , Nadal‐Sala Daniel , Rammer Werner , Rammig Anja , Reineking Björn , Roedig Edna , Sabaté Santi , Steinkamp Jörg , Suckow Felicitas , Vacchiano Giorgio , Wild Jan , Xu Chonggang , Reyer Christopher P. O.
Published: February 2019

Models are pivotal for assessing future forest dynamics under the impacts of changing climate and management practices, incorporating representations of tree growth, mortality, and regeneration. Quantitative studies on the importance of mortality submodels are scarce. We evaluated 15 dynamic vegetation models (DVMs) regarding their sensitivity to different formulations of tree mortality under different degrees of climate change. The set of models comprised eight DVMs at the stand scale, three at the landscape scale, and four typically applied at the continental to global scale. Some incorporate empirically derived mortality models, and others are based on experimental data, whereas still others are based on theoretical reasoning. Each DVM was run with at least two alternative mortality submodels. Model behavior was evaluated against empirical time series data, and then, the models were subjected to different scenarios of climate change. Most DVMs matched empirical data quite well, irrespective of the mortality submodel that was used. However, mortality submodels that performed in a very similar manner against past data often led to sharply different trajectories of forest dynamics under future climate change. Most DVMs featured high sensitivity to the mortality submodel, with deviations of basal area and stem numbers on the order of 10–40% per century under current climate and 20–170% under climate change. The sensitivity of a given DVM to scenarios of climate change, however, was typically lower by a factor of two to three. We conclude that (1) mortality is one of the most uncertain processes when it comes to assessing forest response to climate change, and (2) more data and a better process understanding of tree mortality are needed to improve the robustness of simulated future forest dynamics. Our study highlights that comparing several alternative mortality formulations in DVMs provides valuable insights into the effects of process uncertainties on simulated future forest dynamics.
Storm response of a mixed sand gravel beach ridge plain under falling relative sea levels: A stratigraphic investigation using ground penetrating radar
Authors: Pitman Sebastian J. , Jol Harry M. , Shulmeister James , Hart Deirdre E.
Published: February 2019

Beach ridge stratigraphy can provide an important record of both sustained coastal progradation and responses to events such as extreme storms, as well as evidence of earthquake induced sediment pulses. This study is a stratigraphic investigation of the late Holocene mixed sand gravel (MSG) beach ridge plain on the Canterbury coast, New Zealand. The subsurface was imaged along a 370 m shore‐normal transect using 100 and 200 MHz ground penetrating radar (GPR) antennae, and cored to sample sediment textures. Results show that, seaward of a back‐barrier lagoon, the Pegasus Bay beach ridge plain prograded almost uniformly, under conditions of relatively stable sea level. Nearshore sediment supply appears to have created a sustained sediment surplus, perhaps as a result of post‐seismic sediment pulses, resulting in a flat, morphologically featureless beach ridge plain. Evidence of a high magnitude storm provides an exception, with an estimated event return period in excess of 100 years. Evidence from the GPR sequence combined with modern process observations from MSG beaches indicates that a palaeo‐storm initially created a washover fan into the back‐barrier lagoon, with a large amount of sediment simultaneously moved off the beach face into the nearshore. This erosion event resulted in a topographic depression still evident today. In the subsequent recovery period, sediment was reworked by swash onto the beach as a sequence of berm deposit laminations, creating an elevated beach ridge that also has a modern‐day topographic signature. As sediment supply returned to normal, and under conditions of falling sea level, a beach ridge progradation sequence accumulated seaward of the storm feature out to the modern‐day beach as a large flat, uniform progradation plain. This study highlights the importance of extreme storm events and earthquake pulses on MSG coastlines in triggering high volume beach ridge formation during the subsequent recovery period. © 2019 John Wiley & Sons, Ltd.
Are the male reproductive units of Juniperus drupacea Labill. (Cupressaceae s.str.) a compound, polyaxial inflorescence or a dense cluster of simple, uniaxial pollen cones?
Authors: Dörken Veit Martin
Published: February 2019

The Juniperus Section Caryocedrus (Cupressaceae) is one of the three putatively monophyletic sections of the genus. It is monotypic, presented only by J. drupacea. Male reproductive units of this species show several distinct features distinguishing it distinctly from all other Juniperus species, including an inflorescence‐like arrangement of pollen cones, an increased number of microsporangia per microsporangiophore, and microsporangia attached to the stalk in up to three subsequent rows. The male reproductive units in J. drupacea have been investigated with paraffin technique and SEM. They are hypothesized to represent a distal cluster of densely arranged, simple pollen cones, which are interpreted as being derived from an ancestral condition that is still presented in species of the Section Juniperus. This is assumed to have occurred by a profound reduction of internodes of the fertile shoot axis carrying the pollen cone and a distal shift. The increased number of microsporangia per microsporangiophore may be a response to the decreasing number of pollen cones per tree compensating for the loss of pollen, that occurred during the evolution of inflorescence‐like male reproductive units.
Tailoring bilberry powder functionality through preprocessing and drying
Authors: Eliasson Lovisa , Oliveira Gabriel , Ehrnell Maria , Höglund Evelina , Alminger Marie
Published: February 2019

Berry powders are popular as ingredients in a range of food products, where they naturally provide flavor, color, texture, polyphenols, fiber, and other nutrients. The choices regarding processing techniques and conditions influence the quality attributes of berry powders. The aim of this study was to study the effects on bilberry powder functionalities of applying different preprocessing techniques (purée mixing and juice pressing vs. untreated whole berries) prior to hot air drying and milling. Drying of press cake reduced the drying time by 72% and increased the total apparent phenolic content of the final powder by 44%, as compared to the powder of dried whole berries. The press cake powder showed an easier flowing behavior than the powders from whole berries and puréed berries. Dispersibility (in water and dairy cream) was 60% higher for powders from whole berries and puréed berries, as compared to press cake. The total phenolic content of the dispersed powders was highest for whole berries and puréed berries. Bilberry powder functionality can be modulated through the selection of an appropriate preprocessing technique before drying and milling. This tailors the powder properties into food ingredients ready for different applications, without the need for additives.
Tetravalent Pseudomonas aeruginosa Adhesion Lectin LecA Inhibitor for Enhanced Biofilm Inhibition
Authors: Yu Guangyun , Thies‐Weesie Dominique M. E. , Pieters Roland J.
Published: February 2019

A potent divalent ligand of the Pseudomonas aeruginosa adhesion lectin LecA was elaborated into a tetravalent version. A polyethylene glycol (PEG) spacer was introduced to link two divalent galactosides. Each of the two divalent ligands contained a rigid spacer with a central phenyl group that is bridged by the PEG moiety. The resulting tetravalent ligand was found to bind LecA in the nanomolar range involving all of its sugar (sub)ligands. Analytical ultracentrifugation studies clearly showed that the tetravalent ligand was capable of aggregation the LecA tetramers in contrast to the divalent ligands. The aggregator behavior was found to be of importance in P. aeruginosa biofilm formation inhibition. Despite the weaker affinity it was a considerably better biofilm inhibitor with half inhibitory values around the 28 micromolar range.
The role of wetland coverage within the near‐stream zone in predicting of seasonal stream export chemistry from forested headwater catchments
Authors: Casson Nora J. , Eimers M. Catherine , Watmough Shaun A. , Richardson Murray C.
Published: February 2019

Stream chemistry is often used to infer catchment‐scale biogeochemical processes. However, biogeochemical cycling in the near‐stream zone or hydrologically connected areas may exert a stronger influence on stream chemistry compared with cycling processes occurring in more distal parts of the catchment, particularly in dry seasons and in dry years. In this study, we tested the hypotheses that near‐stream wetland proportion is a better predictor of seasonal (winter, spring, summer, and fall) stream chemistry compared with whole‐catchment averages and that these relationships are stronger in dryer periods with lower hydrologic connectivity. We evaluated relationships between catchment wetland proportion and 16‐year average seasonal flow‐weighted concentrations of both biogeochemically active nutrients, dissolved organic carbon (DOC), nitrate (NO3‐N), total phosphorus (TP), as well as weathering products, calcium (Ca), magnesium (Mg), at ten headwater (<200 ha) forested catchments in south‐central Ontario, Canada. Wetland proportion across the entire catchment was the best predictor of DOC and TP in all seasons and years, whereas predictions of NO3‐N concentrations improved when only the proportion of wetland within the near‐stream zone was considered. This was particularly the case during dry years and dry seasons such as summer. In contrast, Ca and Mg showed no relationship with catchment wetland proportion at any scale or in any season. In forested headwater catchments, variable hydrologic connectivity of source areas to streams alters the role of the near‐stream zone environment, particularly during dry periods. The results also suggest that extent of riparian zone control may vary under changing patterns of hydrological connectivity. Predictions of biogeochemically active nutrients, particularly NO3‐N, can be improved by including near‐stream zone catchment morphology in landscape models.
Human papillomavirus type 8 oncoproteins E6 and E7 cooperate in downregulation of the cellular checkpoint kinase‐1
Authors: Akgül Baki , Kirschberg Matthias , Storey Alan , Hufbauer Martin
Published: February 2019

Human papillomavirus 8 (HPV8) is associated with the development of squamous cell carcinoma (SCC) of the skin. HPV‐infected keratinocytes are able to override normal checkpoint control mechanisms and sustain cell cycle activity, allowing for synthesis of cellular proteins necessary for viral genome amplification. To study how HPV8 may disrupt cell cycle control, we analyzed the impact of HPV8 early gene expression on one of the key regulators of cell cycle and DNA damage response, checkpoint kinase‐1 (CHK1). We found that expression of E1, E1̂E4, E2, E6 or E7 individually did not affect CHK1; however, keratinocytes expressing the complete early genome region (CER) of HPV8 showed a profound loss of CHK1 protein levels, that proved to be mediated by E6E7 co‐expression. Neither CHK1 promoter regulation nor the ubiquitin‐proteasome pathway are involved in HPV8‐mediated CHK1 repression. However, CHK1 protein repression in organotypic skin cultures was paralleled by downregulation of the autophagy marker LC3B. Treatment of HPV8‐CER expressing cells with the autophagy inhibitor Bafilomycin A1 rescued CHK1 expression and led to LC3B accumulation. Taken together, our data implicate that CHK1 autophagic degradation is enhanced by HPV8, which may contribute to the oncogenic potential of the virus.
Cysteine‐Rich Antifungal Proteins from Filamentous Fungi are Promising Bioactive Natural Compounds in Anti‐Candida Therapy
Authors: Galgóczy László , Yap Annie , Marx Florentine
Published: February 2019

The emerging number of life‐threatening invasive fungal infections caused by drug‐resistant Candida strains urges the need for the development and application of fundamentally new and safe antifungal strategies in the clinical treatment. Recent studies demonstrated that the extracellular cysteine‐rich and cationic antifungal proteins (crAFPs) originating from filamentous fungi, and de novo designed synthetic peptide derivatives of these crAFPs provide a feasible basis for this approach. This mini‐review focuses on the global challenges of the anti‐Canidia therapy and on the crAFPs as potential drug candidates to overcome existing problems. The advantages and limitations in the use of crAFPs and peptide derivatives compared to those of conventional antifungal drugs will also be critically discussed.
Catching up to girls: Understanding the gender imbalance in educational attainment within race
Authors: Aucejo Esteban M. , James Jonathan
Published: February 2019

We estimate a sequential model of schooling to assess the major contributing factors to the large gender imbalance in educational attainment within racial groups. First, we find that differences between males and females in measures of early behavior account for the majority of the gender gap for each racial group. Second, we show that black males have the largest response to improvements in family background characteristics, such that equalizing the distribution of family background characteristics for black and white youths reduces the gender gap in college enrollment among black youth by 50%.
In vivo molecular engineering of the urethra for treatment of stress incontinence using novel biomimetic proteoglycans
Authors: Kriete Alicia S. , Ginzburg Natasha , Shah Nima , Huneke Richard B. , Reimold Emily , Prudnikova Katsiaryna , Montgomery Owen , Hou J. Steve , Phillips Evan R. , Marcolongo Michele S.
Published: February 2019

Stress urinary incontinence (SUI), a serious condition which affects ~56% of postmenopausal women, is the involuntary leakage of urine through urethra during physical activity that causes an increase in abdominal pressure. SUI is associated with a decrease in compliance and volume of urethral tissue, likely due to a reduced proteoglycan: collagen ratio in the extracellular matrix and collagen disorganization. Here, we investigated the use of biomimetic proteoglycans (BPGs) to molecularly engineer urethral tissue of New Zealand White rabbits to examine biocompatibility in vivo. BPG concentrations of 50 mg/mL (n = 6, 1 week) and 200 mg/mL (n = 6, 1 week and n = 6, 6 weeks) dissolved in 1× phosphate‐buffered saline (PBS) were injected transurethrally using a 9 French cystoscope, and were compared to PBS‐injected controls (n = 3, 1 week) and non‐injected controls (n = 2, 1 week). Urethral compression pressure measurements confirm BPG injections did not modify normal urethral pressure, as intended. Histological assessment demonstrated biological tolerance of BPGs in urethra and no inflammatory response was detected after 1 and 6 weeks compared to non‐injected controls. Confocal imaging of fluorescently‐labeled BPG injected urethral specimens demonstrated the integration of BPGs into the interstitial connective tissue and confirmed they were still present after 6 weeks. A general decrease of collagen density was exhibited near injection sites which may be due to increased hydration induced by BPGs. Injection of BPGs is a novel approach that demonstrates potential as molecular treatment for SUI and may be able to reverse some of the degenerative tissue changes of individuals affected by this condition. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: 00B: 000–000, 2019. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2409–2418, 2019.
Deciphering the relative roles of matrix metalloproteinase‐ and plasmin‐mediated matrix degradation during capillary morphogenesis using engineered hydrogels
Authors: Beamish Jeffrey A. , Juliar Benjamin A. , Cleveland David S. , Busch Megan E. , Nimmagadda Likitha , Putnam Andrew J.
Published: February 2019

Extracellular matrix (ECM) remodeling is essential for the process of capillary morphogenesis. Here we employed synthetic poly(ethylene glycol) (PEG) hydrogels engineered with proteolytic specificity to either matrix metalloproteinases (MMPs), plasmin, or both to investigate the relative contributions of MMP‐ and plasmin‐mediated ECM remodeling to vessel formation in a 3D‐model of capillary self‐assembly analogous to vasculogenesis. We first demonstrated a role for both MMP‐ and plasmin‐mediated mechanisms of ECM remodeling in an endothelial‐fibroblast co‐culture model of vasculogenesis in fibrin hydrogels using inhibitors of MMPs and plasmin. When this co‐culture model was employed in engineered PEG hydrogels with selective protease sensitivity, we observed robust capillary morphogenesis only in MMP‐sensitive matrices. Fibroblast spreading in plasmin‐selective hydrogels confirmed this difference was due to protease preference by endothelial cells, not due to limitations of the matrix itself. In hydrogels engineered with crosslinks that were dually susceptible to MMPs and plasmin, capillary morphogenesis was unchanged. These findings highlight the critical importance of MMP‐mediated degradation during vasculogenesis and provide strong evidence to justify the preferential selection of MMP‐degradable peptide crosslinkers in synthetic hydrogels used to study vascular morphogenesis and promote vascularization. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2507–2516, 2019.
Association of vaspin rs2236242 gene variants with type 2 diabetes and obesity in a Chinese population: A prospective, single‐center study
Authors: Li Ji , Li Qian , Zhu Ying‐Chun , Wang Ya‐Kun , Gao Cong‐Pu , Li Xiao‐Ying , Ji Tingting , Bai Shou‐Jun
Published: February 2019

Aim

Vaspin is an adipokine separated from visceral fat tissues of obese diabetic rats. This study was to investigate the association between vaspin rs2236242 gene polymorphism and type 2 diabetes mellitus (T2DM) or obesity in a Chinese population.

Materials and Methods

T2DM patients and nondiabetic controls were recruited from Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University (Shanghai, China) from May 1, 2015 to June 30, 2017. Clinicopathologic characteristics were recorded and their blood samples were collected. Serum vaspin levels were detected by enzyme‐linked immunosorbent assay and vaspin rs2236242 genotypes by tetra‐amplification refractory mutation system‐polymerase chain reaction.

Results

Two hundred and ninety‐nine patients with T2DM and 311 controls were recruited at last. The vaspin genotypes of diabetic patients were distinct from nondiabetic controls (χ
2 = 54.611,
p < 0.0001). Genotyping revealed that T2DM patients have a greater prevalence of A allele compared with controls (61.9% vs. 42.1%,
p < 0.0001). A allele was associated with an increased risk of T2DM (odds ratio = 2.23, 95% confidence interval = 1.773–2.804,
p < 0.0001) compared with T allele. The genotype distribution did not differ among nondiabetic subjects with or without obesity. The serum vaspin levels were higher in T2DM patients and obese controls than the nonobese controls, however, the rs2236242 was not found to be significantly related to serum vaspin levels.

Conclusions

Our findings showed the association between vaspin rs2236242 gene variants with obesity and T2DM in a Chinese population. People with rs2236242 A allele had a 2.23‐fold increased risk of T2DM. These findings suggest that vaspin rs2236242 may serve as a potential diagnostic and/or therapeutic targets for T2DM.
The rate of fluid shear stress is a potent regulator for the differentiation of mesenchymal stem cells
Authors: Yue Danyang , Zhang Mengxue , Lu Juan , Zhou Jin , Bai Yuying , Pan Jun
Published: February 2019

We have previously demonstrated that the rate of fluid shear stress (ΔSS) can manipulate the fate of mesenchymal stem cells (MSCs) to osteogenic or chondrogenic cells. However, whether ΔSS is comparable to other two means of induction medium and substrate stiffness that have been proven to be potent in differentiation control is unknown. In this study, we subjected MSCs to 1–7 days of osteogenic or chondrogenic chemical induction, or 1–4 days of 37 or 86 kPa of substrate stiffness induction, followed by 20 min of Fast ΔSS (0–0′) or Slow ΔSS (0–2′), which is a laminar FSS that linearly increased from 0 to 10 dyn/cm
2 in 0 (Fast) or 2 min (Slow) and maintained at 10 dyn/cm
2 for a total of 20 min. We found that 20 min of ΔSS could compete with 5 days' chemical and 2 days' substrate stiffness inductions. Our study confirmed that ΔSS is a powerful tool to control the differentiation of MSCs, which stressed the possible application in MSCs linage specification.
Influence of forkhead box protein 3 polymorphisms (rs2232365, rs3761548) with the outcome of pregnancy: A meta‐analysis
Authors: Hosseini Teshnizi Saeed , Ali‐Hassanzadeh Mohammad , Gharesi‐Fard Behrouz , Kabelitz Dieter , Kalantar Kurosh
Published: February 2019

Dysfunction of regulatory T cells (Tregs) may contribute to certain immune‐related pregnancy complications. Forkhead box protein 3 (FOXP3) is the key transcription factor of Treg. We performed a systematic review and meta‐analysis to evaluate the possible association between FOXP3 polymorphisms −924A/G (rs2232365) and −3279C/A (rs3761548) and immune‐related pregnancy complications. After reviewing 78 fully published studies, 10 studies fulfilled previously defined eligibility criteria and were used for meta‐analysis. Two single nucleotide polymorphisms showed a significant correlation with increased or reduced risk for immune‐related pregnancy complications. For rs3761548, women with allele A were significantly at a higher risk than women carrying allele C (odds ratio = 1.29, 95% confidence interval: 1.20–1.38; p = 0.001). For rs2232365, women with GG or AG genotype were at a higher risk than women with genotype AA, thereby, allele G was significantly associated with a higher risk than allele A. Our meta‐analysis supports the notion that immune‐related pregnancy complications might be linked to genetic variations in the FOXP3 gene.
Metformin protects PC12 cells and hippocampal neurons from H2O2‐induced oxidative damage through activation of AMPK pathway
Authors: Zhao Xia , Zeng Zhiwen , Gaur Uma , Fang Jiankang , Peng Tangming , Li Shuai , Zheng Wenhua
Published: February 2019

Metformin, a first line anti type 2 diabetes drug, has recently been shown to extend lifespan in various species, and therefore, became the first antiaging drug in clinical trial. Oxidative stress due to excess reactive oxygen species (ROS) is considered to be an important factor in aging and related disease, such as Alzheimer's disease (AD). However, the antioxidative effects of metformin and its underlying mechanisms in neuronal cells is not known. In the present study, we showed that metformin, in clinically relevant concentrations, protected neuronal PC12 cells from H2O2‐induced cell death. Metformin signiﬁcantly ameliorated cell death due to H2O2 insult by restoring abnormal changes in nuclear morphology, intracellular ROS, lactate dehydrogenase, and mitochondrial membrane potential induced by H2O2. Hoechst staining assay and flow cytometry analysis revealed that metformin significantly reduced the apoptosis in PC12 cells exposed to H2O2. Western blot analysis further demonstrated that metformin stimulated the phosphorylation and activation of AMP‐activated protein kinase (AMPK) in PC12 cells, while application of AMPK inhibitor compound C, or knockdown of the expression of AMPK by specific small interfering RNA or short hairpin RNA blocked the protective effect of metformin. Similar results were obtained in primary cultured hippocampal neurons. Taken together, these results indicated that metformin is able to protect neuronal cells from oxidative injury, at least in part, via the activation of AMPK. As metformin is comparatively cheaper with much less side effects in clinic, our findings support its potential to be a drug for prevention and treatment of aging and aging‐related diseases.
PD‐1/PD‐L1 pathway: Basic biology and role in cancer immunotherapy
Authors: Salmaninejad Arash , Valilou Saeed Farajzadeh , Shabgah Arezoo Gowhari , Aslani Saeed , Alimardani Malihe , Pasdar Alireza , Sahebkar Amirhossein
Published: February 2019

Over the course of past few years, cancer immunotherapy has been accompanied with promising results. However, preliminary investigations with respect to immunotherapy concentrated mostly on targeting the immune checkpoints, nowadays, emerge as the most efficient strategy to raise beneficial antitumor immune responses. Programmed cell death protein 1 (PD‐1) plays an important role in subsiding immune responses and promoting self‐tolerance through suppressing the activity of T cells and promoting differentiation of regulatory T cells. PD‐1 is considered as an immune checkpoint and protects against autoimmune responses through both induction of apoptosis in antigen‐specific T cells and inhibiting apoptosis in regulatory T cells. Several clinical trials exerting PD‐1 monoclonal antibodies as well as other immune‐checkpoint blockades have had prosperous outcomes and opened new horizons in tumor immunotherapy. Nonetheless, a bulk of patients have failed to respond to these newly emerging immune‐based approach and the survival rate was not satisfying. Additional strategies, especially combination therapies, has been initiated and been further promising. Attempts to identify novel and well‐suited predictive biomarkers are also sensed. In this review, the promotion of cancer immunotherapy targeting PD‐1 immunoinhibitory pathway is discussed.
Berberine attenuates hypoxia‐induced pulmonary arterial hypertension via bone morphogenetic protein and transforming growth factor‐β signaling
Authors: Chen Mingxing , Shen Hui , Zhu Linlin , Yang Hongfeng , Ye Peng , Liu Pengfei , Gu Yue , Chen Shaoliang
Published: February 2019

Hypoxia‐induced excessive pulmonary artery smooth muscle cell (PASMC) proliferation plays an important role in the pathology of pulmonary arterial hypertension (PAH). Berberine (BBR) is reported as an effective antiproliferative properties applied in clinical. However, the effect of BBR on PAH remains unclear. In the present study, we elucidated the protective effects of BBR against abnormal PASMC proliferation and vascular remodeling in chronic hypoxia‐induced hearts. Furthermore, the potential mechanisms of BBR were investigated. For this purpose, C57/BL6 mice were exposed to chronic hypoxia for 4 weeks to mimic severe PAH. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased the right ventricular systolic pressure (RVSP), the right ventricle/left ventricle plus septum RV/(LV + S) weight ratio, and the median width of pulmonary arterioles. BBR attenuated the elevations in RVSP and RV/(LV + S) and mitigated pulmonary vascular structure remodeling. BBR also suppressed the hypoxia‐induced increases in the expression of proliferating cell nuclear antigen (PCNA) and of α‐smooth muscle actin. Furthermore, administration of BBR significantly increased the expression of bone morphogenetic protein type II receptor (BMPR‐II) and its downstream molecules P‐smad1/5 and decreased the expression of transforming growth factor‐β (TGF‐β) and its downstream molecules P‐smad2/3. Moreover, peroxisome proliferator‐activated receptor γ expression was significantly decreased in the hypoxia group, and this decrease was reversed by BBR treatment. Our study demonstrated that the protective effect of BBR against hypoxia‐induced PAH in a mouse model may be achieved through altered BMPR‐II and TGF‐β signaling.
Middle cerebral artery peak systolic velocity in perinatal cytomegalovirus infection
Authors: Duncan Jose R. , Schenone Mauro H. , Argoti Pedro S. , Mari Giancarlo
Published: February 2019

A middle cerebral artery peak systolic velocity value (MCA‐PSV) persistently greater than 1.5 times the median of the normal population is utilized to detect moderate and severe anemia in fetuses at risk. Cytomegalovirus (CMV) is the most common perinatal infection and can cause fetal anemia. We present four cases with CMV perinatal infection. Although their MCA‐PSV values were the highest recorded in normal as well as in anemic fetuses, only two of them developed moderate or severe anemia. These findings suggest that high MCA‐PSV values in cases with perinatal CMV infection may have a different pathophysiologic mechanism than anemia.
Evaluation of X‐ray tomography contrast agents: A review of production, protocols, and biological applications
Authors: Koç Mümin Mehmet , Aslan Naim , Kao Alexander P. , Barber Asa H.
Published: February 2019

X‐ray computed tomography is a strong tool that finds many applications both in medical applications and in the investigation of biological and nonbiological samples. In the clinics, X‐ray tomography is widely used for diagnostic purposes whose three‐dimensional imaging in high resolution helps physicians to obtain detailed image of investigated regions. Researchers in biological sciences and engineering use X‐ray tomography because it is a nondestructive method to assess the structure of their samples. In both medical and biological applications, visualization of soft tissues and structures requires special treatment, in which special contrast agents are used. In this detailed report, molecule‐based and nanoparticle‐based contrast agents used in biological applications to enhance the image quality were compiled and reported. Special contrast agent applications and protocols to enhance the contrast for the biological applications and works to develop nanoparticle contrast agents to enhance the contrast for targeted drug delivery and general imaging applications were also assessed and listed.
Efficient Synthesis of New 2H‐Chromene Retinoids Hybrid Derivatives by Suzuki Cross‐coupling Reactions
Authors: Kaoukabi Asma , Belachemi Larbi , Lahcini Mohammed , Massuard Marie‐Claude Viaud , Croix Cécile
Published: February 2019

In an attempt to improve anticancer activity, a series of retinoids–chromene hybrids was described. The novel heterocyclic chromene–retinoids hybrid including oxygen as a heteroatom in a six‐membered cyclic ring (2H‐chromene or 2H‐1‐benzopyran) was designed and synthesized by introducing different groups such as an aromatic or styrylphenyl ring in 6‐position of 2H‐chromene. These novel compounds were synthesized by using the efficient cascades one‐pot process involving Wittig–Horner–Emmons reaction and Suzuki–Miyaura cross‐coupling pallado‐catalyzed reactions with 60% to 90% overall yields. These new compounds were tested against glioblastoma multiforme brain cancer, medulloblastoma, neuroblastoma cell lines, and breast cancer MCF‐7 cell lines. Two of them exhibited an appreciable anti‐tumor activity in the low micromolar range, which opens new perspectives for therapeutic application on humans.
Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy
Authors: Wu Jianming , Mishra Hemant K , Walcheck Bruce
Published: February 2019

Human NK cell antitumor activities involve Ab-dependent cell-mediated cytotoxicity (ADCC), which is a key mechanism of action for several clinically successful tumor-targeting therapeutic mAbs. Human NK cells exclusively recognize these Abs by the Fcγ receptor CD16A (FcγRIIIA), one of their most potent activating receptors. Unlike other activating receptors on NK cells, CD16A undergoes a rapid down-regulation in expression by a proteolytic process following NK cell activation with various stimuli. In this review, the role of a disintegrin and metalloproteinase-17 (ADAM17) in CD16A cleavage and as a regulatory checkpoint is discussed. Several studies have examined the effects of inhibiting ADAM17 or CD16A cleavage directly during NK cell engagement of Ab-coated tumor cells, which resulted in strengthened Ab tethering, decreased tumor cell detachment, and enhanced CD16A signaling and cytokine production. However, the effects of either manipulation on ADCC have varied between studies, which may be due to dissimilar assays and the contribution of different killing processes by NK cells. Of importance is that NK cells under various circumstances, including in the tumor microenvironment of patients, down-regulate CD16A and this appears to impair their function. Considerable progress has been made in the development of ADAM17 inhibitors, including human mAbs that have advantages of high specificity and increased half-life in vivo. These inhibitors may provide a therapeutic means of increasing ADCC potency and/or antitumor cytokine production by NK cells in an immunosuppressive tumor microenvironment, and if used in combination with tumor-targeting Abs or NK cell-based adoptive immunotherapies may improve their efficacy.