bluuebunny/crossref_metadata_2025 huggingface dataset:
Advances in targeting co‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy
Authors: Kean Leslie S. , Turka Laurence A. , Blazar Bruce R.
Published: March 2017

In the past decade, the power of harnessing T‐cell co‐signaling pathways has become increasingly understood to have significant clinical importance. In cancer immunotherapy, the field has concentrated on two related modalities: First, targeting cancer antigens through highly activated chimeric antigen T cells (CAR‐Ts) and second, re‐animating endogenous quiescent T cells through checkpoint blockade. In each of these strategies, the therapeutic goal is to re‐ignite T‐cell immunity, in order to eradicate tumors. In transplantation, there is also great interest in targeting T‐cell co‐signaling, but with the opposite goal: in this field, we seek the Yin to cancer immunotherapy's Yang, and focus on manipulating T‐cell co‐signaling to induce tolerance rather than activation. In this review, we discuss the major T‐cell signaling pathways that are being investigated for tolerance induction, detailing preclinical studies and the path to the clinic for many of these molecules. These include blockade of co‐stimulation pathways and agonism of coinhibitory pathways, in order to achieve the delicate state of balance that is transplant tolerance: a state which guarantees lifelong transplant acceptance without ongoing immunosuppression, and with preservation of protective immune responses. In the context of the clinical translation of immune tolerance strategies, we discuss the significant challenge that is embodied by the fact that targeted pathway modulators may have opposing effects on tolerance based on their impact on effector vs regulatory T‐cell biology. Achieving this delicate balance holds the key to the major challenge of transplantation: lifelong control of alloreactivity while maintaining an otherwise intact immune system.
New checkpoints in cancer immunotherapy
Authors: Ni Ling , Dong Chen
Published: March 2017

Immune responses must be fine‐tuned to allow effective clearance of invading pathogens, while maintain tolerance to self‐antigens. T cells are the major effector cells for fighting and killing tumor cells. Immune checkpoints play a pivotal role in T cell activation, and determine the functional outcome of T cell receptor (TCR) signaling. The blockade of immune checkpointsCTLA‐4 andPD‐1 has already been one of the most successful cancer immunotherapies. In this review, we will focus on three novel inhibitory B7 family checkpoint molecules, B7‐H3, B7S1 andVISTA. The aim of this article is to summarize their expressions in tumors as well as their roles in controlling and suppressing T cell immune responses and anti‐tumor immunity. These pathways may be explored in future cancer immunotherapy.
Immunoregulatory functions of VISTA
Authors: Nowak Elizabeth C. , Lines J. Louise , Varn Frederick S. , Deng Jie , Sarde Aurelien , Mabaera Rodwell , Kuta Anna , Le Mercier Isabelle , Cheng Chao , Noelle Randolph J.
Published: March 2017

Utilization of negative checkpoint regulators (NCRs) for cancer immunotherapy has garnered significant interest with the completion of clinical trials demonstrating efficacy. While the results of monotherapy treatments are compelling, there is increasing emphasis on combination treatments in an effort to increase response rates to treatment. One of the most recently discovered NCRs is VISTA (V‐domain Ig‐containing Suppressor of T cell Activation). In this review, we describe the functions of this molecule in the context of cancer immunotherapy. We also discuss factors that may influence the use of anti‐VISTA antibody in combination therapy and how genomic analysis may assist in providing indications for treatment.
Viewing Siglecs through the lens of tumor immunology
Authors: Fraschilla Isabella , Pillai Shiv
Published: March 2017

Many Siglecs function as inhibitory receptors on innate and adaptive immune cells and may contribute to the attenuation of immune responses to tumors. Siglec 9 on neutrophils and Siglec 7 on NK cells are prominent examples of inhibitory Siglecs that can potentially dampen anti‐tumor immunity. CD169 is a Siglec that may function as an adhesion molecule and a facilitator of the recognition and internalization of sialic acid decorated apoptotic bodies and exosomes derived from tumors. It can potentially contribute to both the attenuation as well as the facilitation of anti‐tumor immunity. Siglecs have been best studied in the tumor context in animal models of cancer. Modulators of Siglec function are likely to be developed and investigated clinically in a cancer context over the next few years.
The CD47‐SIRPα signaling axis as an innate immune checkpoint in cancer
Authors: Matlung Hanke L. , Szilagyi Katka , Barclay Neil A. , van den Berg Timo K.
Published: March 2017

Immune checkpoint inhibitors, including those targeting CTLA‐4/B7 and the PD‐1/PD‐L1 inhibitory pathways, are now available for clinical use in cancer patients, with other interesting checkpoint inhibitors being currently in development. Most of these have the purpose to promote adaptive T cell‐mediated immunity against cancer. Here, we review another checkpoint acting to potentiate the activity of innate immune cells towards cancer. This innate immune checkpoint is composed of what has become known as the ‘don't‐eat me’ signal CD47, which is a protein broadly expressed on normal cells and often overexpressed on cancer cells, and its counter‐receptor, the myeloid inhibitory immunoreceptor SIRPα. Blocking CD47‐SIRPα interactions has been shown to promote the destruction of cancer cells by phagocytes, including macrophages and neutrophils. Furthermore, there is growing evidence that targeting of the CD47‐SIRPα axis may also promote antigen‐presenting cell function and thereby stimulate adaptive T cell‐mediated anti‐cancer immunity. The development of CD47‐SIRPα checkpoint inhibitors and the potential side effects that these may have are discussed. Collectively, this identifies the CD47‐SIRPα axis as a promising innate immune checkpoint in cancer, and with data of the first clinical studies with CD47‐SIRPα checkpoint inhibitors expected within the coming years, this is an exciting and rapidly developing field.
The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets
Authors: Allard Bertrand , Longhi Maria Serena , Robson Simon C. , Stagg John
Published: March 2017

Cancers are able to grow by subverting immune suppressive pathways, to prevent the malignant cells as being recognized as dangerous or foreign. This mechanism prevents the cancer from being eliminated by the immune system and allows disease to progress from a very early stage to a lethal state. Immunotherapies are newly developing interventions that modify the patient's immune system to fight cancer, by either directly stimulating rejection‐type processes or blocking suppressive pathways. Extracellular adenosine generated by the ectonucleotidases CD39 and CD73 is a newly recognized “immune checkpoint mediator” that interferes with anti‐tumor immune responses. In this review, we focus on CD39 and CD73 ectoenzymes and encompass aspects of the biochemistry of these molecules as well as detailing the distribution and function on immune cells. Effects of CD39 and CD73 inhibition in preclinical and clinical studies are discussed. Finally, we provide insights into potential clinical application of adenosinergic and other purinergic‐targeting therapies and forecast how these might develop in combination with other anti‐cancer modalities.
Co‐inhibitory blockade while preserving tolerance: checkpoint inhibitors for glioblastoma
Authors: Lucca Liliana E. , Hafler David A.
Published: March 2017

The introduction of immunotherapy with checkpoint receptor blockade has changed the treatment of advanced cancers, at times inducing prolonged remission. Nevertheless, the success rate of the approach is variable across patients and different tumor types, and treatment is often accompanied by severe immune‐related side effects, suggesting the importance of co‐inhibitory pathway for both prevention of autoimmunity and failure of tumor rejection. A better understanding of how to uncouple anti‐tumor activity from loss of self‐tolerance is necessary to increase the therapeutic efficacy of checkpoint immunotherapy. In this review, we describe basic concepts of T‐cell exhaustion that occur in cancer, highlighting the role of co‐inhibitory receptors in contributing to this process while preventing immunopathology. By providing an overview of the current therapeutic success and immune‐related burden of secondary effects of checkpoint immunotherapy, we illustrate the “double‐edged sword” related to interference with immune‐regulatory pathways. Finally, since achieving tumor rejection while preserving self‐tolerance is particularly important for the central nervous system, we analyze the case for checkpoint immunotherapy in glioblastoma, the most common adult brain tumor.
Potential targeting of B7‐H4 for the treatment of cancer
Authors: Podojil Joseph R. , Miller Stephen D.
Published: March 2017

Observations noting the presence of white blood cell infiltrates within tumors date back more than a century, however the cellular and molecular mechanisms regulating tumor immunity continue to be elucidated. The recent successful use of monoclonal antibodies to block immune regulatory pathways to enhance tumor‐specific immune responses for the treatment of cancer has encouraged the identification of additional immune regulatory receptor/ligand pathways. Over the past several years, a growing body of data has identified B7‐H4 (VTCN1/B7x/B7S1) as a potential therapeutic target for the treatment of cancer. The potential clinical significance of B7‐H4 is supported by the high levels of B7‐H4 expression found in numerous tumor tissues and correlation of the level of expression on tumor cells with adverse clinical and pathologic features, including tumor aggressiveness. The biological activity of B7‐H4 has been associated with decreased inflammatory CD4+ T‐cell responses and a correlation between B7‐H4‐expressing tumor‐associated macrophages and FoxP3+ regulatory T cells (Tregs) within the tumor microenvironment. Since B7‐H4 is expressed on tumor cells and tumor‐associated macrophages in various cancer types, therapeutic blockade of B7‐H4 could favorably alter the tumor microenvironment allowing for antigen‐specific clearance tumor cells. The present review highlights the therapeutic potential of targeting B7‐H4.
Wide‐range thermometry based on green up‐conversion luminescence of K3LuF6:Yb3+/Er3+ bulk oxyfluoride glass ceramics
Authors: Cao JiangKun , Hu FangFang , Chen LiPing , Guo Hai , Duan Changkui , Yin Min
Published: March 2017

Yb3+/Er3+ ions codoped bulk glass ceramics (GC) with embedded monoclinic K3LuF6 nanocrystals are reported for potential temperature‐sensing application by using the fluorescence intensity ratio method. Such GC with good transparency and enhanced up‐conversion were prepared by the simple conversional melt‐quenching method and subsequent annealing process. Optical, structural, and temperature‐sensing up‐conversion properties were characterized systematically. Optical spectroscopy analysis confirms the incorporation of Yb3+/Er3+ into the K3LuF6 crystalline lattice, resulting in enhanced up‐conversion luminescence. Compared to other Er3+‐doped typical systems, Er3+ ions in K3LuF6 GC present large energy gap (870 cm−1) and high relative sensitivity (37.6 × 10−4 K−1 at 625 K), revealing that K3LuF6:Yb3+/Er3+ GC can be excellent candidates for optical thermometers.
Experimental and first‐principles study of Ti–C–O system: Interplay of thermodynamic and structural properties
Authors: Jiang Bo , Xiao Jiusan , Huang Kai , Hou Jungang , Jiao Shuqiang , Zhu Hongmin
Published: March 2017

The thermodynamic properties and vacancy formation mechanism of Ti–C–O system were investigated by means of empirical calorimetry method and first‐principles calculations. The heat of combustion of titanium oxycarbides (TiC1−xOx, 0≤x≤1) solid solution were first measured by burning the materials in oxygen bomb calorimeter through sophisticated design experimental environment. The mixing enthalpy of the reaction (1−x)TiC + xTiO=TiC1−xOx was further calculated based on the measured data. Mixing enthalpy was also calculated via efficient first‐principles method based on the density functional theory. The vacancies in TiC1−xOx were described as two kinds of models that are disordered and segregated vacancies in titanium oxycarbides solid solution. The calculation results with segregation model show good agreement with the calorimetric results. The heat capacity values were further calculated to deduce the mixing and formation Gibbs free energy. The additive law of the heat capacity and entropy means that the structure of titanium oxycarbides tends to be in order, and this result shows a good agreement with the segregated model in TiC1−xOx. These results are explained on the basis of the interplay between thermodynamic and structural properties, which offered the important theoretic foundation for the novel titanium production process.
Electromechanical properties of CaZrO3 modified (K,Na)NbO3‐based lead‐free piezoceramics under uniaxial stress conditions
Authors: Wang Ke , Yao Fang‐Zhou , Koruza Jurij , Cheng Li‐Qian , Schader Florian H. , Zhang Mao‐Hua , Rödel Jürgen , Li Jing‐Feng , Webber Kyle G.
Published: March 2017

Piezoelectric actuators are typically preloaded with a modest mechanical compressive stress during actuation to reduce cracking and allow for operation in the dynamic range. In addition, actuators are required to carry out mechanical work during operation, resulting in a nonlinear relationship between stress and actuation voltage. In fact, mechanical loading can significantly impact the electromechanical performance of lead‐free piezoelectrics. Herein, we report the dependence of electromechanical properties of CaZrO3 modified (K,Na)NbO3‐based lead‐free piezoceramics on uniaxial compressive stress, comparing to their lead‐based counterparts. It is demonstrated that increased non‐180° domain switching enhances the strain output at a moderate stress of approximately −50 MPa from room temperature to 150°C. Larger uniaxial stress, however, is found to suppress ferroelectric domain switching, resulting in the continuous strain and polarization decrease.
Microstructure evolution and thermomechanical properties of plasma‐sprayed Yb2SiO5 coating during thermal aging
Authors: Zhong Xin , Niu Yaran , Li Hong , Zeng Yi , Zheng Xuebin , Ding Chuanxian , Sun Jinliang
Published: March 2017

Rare‐earth monosilicates (RE2SiO5, RE: rare‐earth elements), such as Yb2SiO5, have been developed for potential application as environmental barrier coating (EBC) materials. Yb2SiO5 coating would experience microstructure evolution under high‐temperature environment and accordingly its thermomechanical properties would be altered. In this study, Yb2SiO5 coating was fabricated by atmospheric plasma spray technique. The phase stability and microstructure change before and after thermal aging at 1300°C, 1400°C, and 1500°C were investigated. The changes in mechanical and thermal properties were characterized. The results showed that the as‐sprayed coating was mainly composed of Yb2SiO5 with a small amount of Yb2O3 and amorphous phase. Defects in the coating, including interfaces, pores, and microcracks, were greatly reduced with grain growth after thermal treatment. Thermal aging significantly modified the thermal and mechanical properties of the coating. The average CTE was increased by 13.1%, and the hardness and elastic modulus was increased by 42.4% and 49.4%, respectively, after thermal aging at 1500°C for 50 hour. The thermal conductivity of thermal‐aged coating was much higher than that of the as‐sprayed coating, which was still less than 2 W/(m·K). The influence of coating microstructure on the properties was analyzed and related to the failure mechanism of EBCs.
Cold sintering process of Li1.5Al0.5Ge1.5(PO4)3 solid electrolyte
Authors: Berbano Seth S. , Guo Jing , Guo Hanzheng , Lanagan Michael T. , Randall Clive A.
Published: March 2017

The recently developed technique of cold sintering process (CSP) enables densification of ceramics at low temperatures, i.e., <300°C. CSP employs a transient aqueous solvent to enable liquid phase‐assisted densification through mediating the dissolution‐precipitation process under a uniaxial applied pressure. Using CSP in this study, 80% dense Li1.5Al0.5Ge1.5(PO4)3 (LAGP) electrolytes were obtained at 120°C in 20 minutes. After a 5 minute belt furnace treatment at 650°C, 50°C above the crystallization onset, Li‐ion conductivity was 5.4 × 10−5 S/cm at 25°C. Another route to high ionic conductivities ~10−4 S/cm at 25°C is through a composite LAGP ‐ (PVDF‐HFP) co‐sintered system that was soaked in a liquid electrolyte. After soaking 95, 90, 80, 70, and 60 vol% LAGP in 1 M LiPF6 EC‐DMC (50:50 vol%) at 25°C, Li‐ion conductivities were 1.0 × 10−4 S/cm at 25°C with 5 to 10 wt% liquid electrolyte. This paper focuses on the microstructural development and impedance contributions within solid electrolytes processed by (i) Crystallization of bulk glasses, (ii) CSP of ceramics, and (iii) CSP of ceramic‐polymer composites. CSP may offer a new route to enable multilayer battery technology by avoiding the detrimental effects of high temperature heat treatments.
Crystallization, mechanical, and optical properties of transparent, nanocrystalline gahnite glass‐ceramics
Authors: Molla Atiar R. , Rodrigues Alisson M. , Singh Shiv Prakash , Lancelotti Ricardo Felipe , Zanotto Edgar D. , Rodrigues Ana C.M. , Reza Dousti Mohammad , de Camargo Andrea S.S. , Magon Claudio José , Silva Igor D′Anciães Almeida
Published: March 2017

This paper describes the preparation of a transparent glass‐ceramic from the SiO2‐K2O‐ZnO‐Al2O3‐TiO2 system containing a single crystalline phase, gahnite (ZnAl2O4). TiO2 was used as a nucleating agent for the heat‐induced precipitation of gahnite crystals of 5‐10 nm. The evolution of the ZnAl2O4 spinel structure through the gradual formation of Al‐O bonds was examined by infrared spectroscopy. The dark brown color of the transparent precursor glass and glass‐ceramic was eliminated using CeO2. The increase in transparency of the CeO2‐doped glass and glass‐ceramics was demonstrated by UV‐visible absorption spectroscopy. EPR measurements confirmed the presence of Ce3+ ions, indicating that CeO2 was effective in eliminating the brown color introduced by Ti3+ ions via oxidation to Ti+4. The hardness of the glass‐ceramic was 30% higher than that of the as‐prepared glasses. This work offers key guidelines to produce hard, transparent glass‐ceramics which may be potential candidates for a variety of technological applications, such as armor and display panels.
TiO2–BaTiO3 nanocomposite for electron capture in dye‐sensitized solar cells
Authors: Asgari Moghaddam Hatameh , Mohammadi Mohammad Reza
Published: March 2017

Different compositions of TiO2–BaTiO3 nanocomposites are synthesized with various weight ratios for dye‐sensitized solar cell (DSSC) applications. TiO2 and BaTiO3 nanoparticles (NPs) are synthesized by sol‐gel and solvothermal methods, respectively and are employed as the photoanode electrodes. BaTiO3 NPs have pure cubic perovskite crystal structure with an average size of 20‐40 nm, while TiO2 NPs show pure anatase phase with 15‐30 nm size. The power conversion efficiency (PCE) enhancement of the cells is first attained by controlling the thickness of the films for light harvesting improvement. The fabricated DSSC composed of pure BaTiO3 NPs with an optimal thickness of 25 μm shows efficiency of 6.83%, whereas that made of pure TiO2 NPs with 14 μm thickness has cell efficiency of 7.24%. Further improvement of cell efficiency is achieved by preparation of binary oxide nanocomposites using TiO2 and BaTiO3 NPs with various weight ratios. The highest PCE of 9.40% is obtained for the nanocomposite with TiO2:BaTiO3=85:15 (wt%). The enhancement is assigned to less recombination of photo‐generated electrons and higher incident photon to current conversion yield as a result of rapid charge collection and higher dye sensitization.
The long shadow of senescence: age impacts survival and territory defense in loons
Authors: Piper Walter H. , Brunk Kristin M. , Flory Joel A. , Meyer Michael W.
Published: March 2017

Senescence, increased mortality that occurs among animals of advanced age, impacts behavior and ecology in many avian species. We investigated actuarial, reproductive, and behavioral senescence using capture, marking, and resighting data from a 26‐year study of common loons Gavia immer. Territorial residents of both sexes exhibited high annual survival (0.94) until their mid 20s, at which point survival fell to 0.76 and 0.77 in males and females, respectively. Sexual symmetry in actuarial senescence is somewhat surprising in this species, because males make a substantially greater investment in territory defense and chick‐rearing and because males engage in lethal contests for territory ownership. Survival of displaced breeders (0.80) was lower than that of territorial residents in both young and old individuals. Old males and females also experienced slightly higher annual probability of eviction (0.16 for males; 0.17 for females) than prime‐aged breeders (0.13 for both sexes), indicating senescence in territory defense. Prime‐aged males reclaimed territories at a high rate (0.49), in contrast to females of the same age (0.33). However, old males resettled with success (0.35) similar to old females (0.31), suggesting that males decline in competitive ability as they age. Nonetheless males, but not females, showed an apparent increase in breeding success over the entire lifetime, a possible indication that very old males make a terminal investment in reproductive output at the cost of survival.
Polymerization Mode of Self‐Adhesive, Dual‐Cured Dental Resin Cements Light Cured Through Various Restorative Materials
Authors: Shim Ji Suk , Kang Jeong Kyung , Jha Nayansi , Ryu Jae Jun
Published: March 2017

Objective

The aim of this study was to investigate the polymerization mode of self‐adhesive, dual‐cured resin cements light‐cured through overlying materials with different degree of translucency by measuring the degree of conversion (DC).

Materials and Methods

Three kinds of self‐adhesive, dual‐cured resin cements (G‐CEM LinkAceTM, Maxcem EliteTM, and BisCem®) were light‐cured through three different restorative materials that included porcelain‐fused metal (PFM), zirconia, and lithium disilicate. Polymerization kinetics were continuously evaluated using infrared spectroscopy after 0, 5, 10, and 30 min and 2 weeks of mixing. Data were statistically analyzed using two‐way analysis of variance (ANOVA), one‐way ANOVA, and Tukey's multiple‐comparison test (α = 0.05).

Results

Regardless of the kind of resin cement, the light‐cured groups showed higher DC than did the autopolymerization group under PFM at any point of time (p < 0.05). The time taken by the cements to achieve statistically similar DC between the zirconia and lithium disilicate groups increased in the following order: G‐CEM LinkAceTM, BisCem®, and Maxcem EliteTM (p < 0.05).

Conclusions

The degree of translucency of the restorative material can be a significant variable determining the polymerization aspects of self‐adhesive, dual‐cured resin cements. The resin cements light‐cured through lithium disilicate and zirconia showed higher DC than that shown by cements cured under PFM at any measurement time. The lithium disilicate and zirconia groups showed differences in the early stage of polymerization for G‐CEM LinkAceTM and BisCem®; however, the differences diminished at 2 weeks.

CLINICAL SIGNIFICANCE

Chemical polymerization is not sufficient to cause the resin cement to achieve the highest polymerization not only in early stage, but also in late stage of polymerization. The sensitivity to the intensity of the light was different for each resin cement. Special clinical steps to compensate for the attenuated light intensity seem to be necessary for the resin cements which are susceptible to light intensity. (J Esthet Restor Dent 29:209–214, 2017)
Use of Highly Specific Molecular Markers Reveals Positive Correlation between Abundances of Mesodinium cf. major and Its Preferred Prey, Teleaulax amphioxeia, During Red Water Blooms in the Columbia River Estuary
Authors: Herfort Lydie , Maxey Katie , Voorhees Ian , Simon Holly M. , Grobler Kolette , Peterson Tawnya D. , Zuber Peter
Published: March 2017

In a previous study, Teleaulax amphioxeia—the preferred prey of Mesodinium in the Columbia River estuary—were undetectable within intense annual blooms, suggesting blooms are prey‐limited or prey are acquired outside of bloom patches. We used a novel molecular approach specifically targeting the prey (i.e., Unique Sequence Element [USE] within the ribosomal RNA 28S D2 regions of T. amphioxeia nucleus and nucleomorph) in estuarine water samples acquired autonomously with an Environmental Sample Processor integrated within a monitoring network (ESP‐SATURN). This new approach allowed for both more specific detection of the prey and better constraint of sample variability. A positive correlation was observed between abundances of M. cf. major and T. amphioxeia during bloom periods. The correlation was stronger at depth (> 8.2 m) and weak or nonexistent in the surface, suggesting that predator–prey dynamics become uncoupled when stratification is strong. We confirmed exclusive selectivity for T. amphioxeia by M. cf. major and observed the incorporation of the prey nucleus into a 4‐nuclei complex, where it remained functionally active. The specific biomarker for T. amphioxeia was also recovered in M. cf. major samples from a Namibian coastal bloom, suggesting that a specific predator–prey relationship might be widespread between M. cf. major and T. amphioxeia.
Differences in the Detection of BrdU/EdU Incorporation Assays Alter the Calculation for G1, S, and G2 Phases of the Cell Cycle in Trypanosomatids
Authors: da Silva Marcelo Santos , Muñoz Paula Andrea Marin , Armelin Hugo Aguirre , Elias Maria Carolina
Published: March 2017

Trypanosomatids are the etiologic agents of various infectious diseases in humans. They diverged early during eukaryotic evolution and have attracted attention as peculiar models for evolutionary and comparative studies. Here, we show a meticulous study comparing the incorporation and detection of the thymidine analogs BrdU and EdU in Leishmania amazonensis, Trypanosoma brucei, and Trypanosoma cruzi to monitor their DNA replication. We used BrdU‐ and EdU‐incorporated parasites with the respective standard detection approaches: indirect immunofluorescence to detect BrdU after standard denaturation (2 M HCl) and “click” chemistry to detect EdU. We found a discrepancy between these two thymidine analogs due to the poor detection of BrdU, which is reflected on the estimative of the duration of the cell cycle phases G1, S, and G2. To solve this discrepancy, we increase the exposure of incorporated BrdU using different concentrations of HCl. Using a new value for HCl concentration, we re‐estimated the phases G1, S, G2 + M, and cytokinesis durations, confirming the values found by this approach using EdU. In conclusion, we suggest that the studies using BrdU with standard detection approach, not only in trypanosomatids but also in others cell types, should be reviewed to ensure an accurate estimation of DNA replication monitoring.
Daclatasvir and asunaprevir treatment in patients with severe liver fibrosis by hepatitis C virus genotype 1b infection: Real‐world data
Authors: Ishigami Masatoshi , Hayashi Kazuhiko , Honda Takashi , Kuzuya Teiji , Ishizu Yoji , Ishikawa Tetsuya , Nakano Isao , Urano Fumihiro , Kumada Takashi , Yoshioka Kentaro , Goto Hidemi , Hirooka Yoshiki
Published: March 2017

Background and Aim

In this study, we investigated the real‐world data of the first approved interferon‐free regimen in Japan: daclatasvir and asunaprevir in chronic hepatitis C patients with severe fibrosis.

Methods

Among 924 patients registered in our multicenter study, 535 patients were defined as having severe fibrosis with Fib‐4 index ≧ 3.25 and were included in this study. We investigated antiviral effect and factors associated with sustained viral response 12 (SVR12), and the additional effects on serum α‐fetoprotein and albumin levels by eradicating virus in patients who attained SVR were investigated. In statistical analysis, P < 0.05 was considered as significant levels.

Results

Antiviral effect was lower in patients with severe fibrosis at 8 and 12 weeks after start of the treatment (96.3%, 97.1% with severe fibrosis vs 99.5%, 99.2% without severe fibrosis, P = 0.002 and P = 0.036, respectively), and more early relapse (SVR4; 90.4% with severe fibrosis vs 95.4% without fibrosis, P = 0.008) was seen in patients with severe fibrosis; however, there were no differences in SVR12 and SVR24. In the safety profiles, discontinuation rate due to liver injury (2.8% with severe fibrosis vs 3.3% without severe fibrosis) or other causes of discontinuation was not different between two groups. Serum α‐fetoprotein significantly decreased, and serum albumin levels significantly increased as early as 4 weeks after the start of treatment.

Conclusion

Although the antiviral effect was slightly lower in patients with severe fibrosis compared with those without, treatment with daclatasvir and asunaprevir is basically an effective and well‐tolerable treatment in these populations.
Glucose concentrations modulate brain‐derived neurotrophic factor responsiveness of neurones in the paraventricular nucleus of the hypothalamus
Authors: McIsaac W. , Ferguson A. V.
Published: March 2017

The hypothalamic paraventricular nucleus (PVN) is critical for normal energy balance and has been shown to contain high levels of both brain‐derived neurotrophic factor (BDNF) and tropomyosin‐receptor kinase B mRNA. Microinjections of BDNF into the PVN increase energy expenditure, suggesting that BDNF plays an important role in energy homeostasis through direct actions in this nucleus. The present study aimed to examine the postsynaptic effects of BDNF on the membrane potential of PVN neurones, and also to determine whether extracellular glucose concentrations modulated these effects. We used hypothalamic PVN slices from male Sprague‐Dawley rats to perform whole cell current‐clamp recordings from PVN neurones. BDNF was bath applied at a concentration of 2 nmol L‐1 and the effects on membrane potential determined. BDNF caused depolarisations in 54% of neurones (n=25; mean±SEM, 8.9±1.2 mV) and hyperpolarisations in 23% (n=11; −6.7±1.4 mV), whereas the remaining cells were unaffected. These effects were maintained in the presence of tetrodotoxin (n=9; 56% depolarised, 22% hyperpolarised, 22% nonresponders), or the GABAa antagonist bicuculline (n=12; 42% depolarised, 17% hyperpolarised, 41% nonresponders), supporting the conclusion that these effects on membrane potential were postsynaptic. Current‐clamp recordings from PVN neurones next examined the effects of BDNF on these neurones at varying extracellular glucose concentrations. Larger proportions of PVN neurones hyperpolarised in response to BDNF as the glucose concentrations decreased [10 mmol L−1 glucose 23% (n=11) of neurones hyperpolarised, whereas, at 0.2 mmol L−1 glucose, 71% showed hyperpolarising effects (n=12)]. Our findings reveal that BDNF has direct GABAA independent effects on PVN neurones, which are modulated by local glucose concentrations. The latter observation further emphasises the critical importance of using physiologically relevant conditions in an investigation of the central pathways involved in the regulation of energy homeostasis.
Pure optic ataxia and visual hemiagnosia – extending the dual visual hypothesis
Authors: Meichtry Jurka R. , Cazzoli Dario , Chaves Silvia , von Arx Sebastian , Pflugshaupt Tobias , Kalla Roger , Bassetti Claudio L. , Gutbrod Klemens , Müri René M.
Published: March 2017

Goodale and Milner's two visual system hypothesis is an influential model for the understanding of the primate visual system. Lesions of either the ventral (occipito‐temporal) or the dorsal (occipito‐parietal) stream produce distinct and dissociated syndromes in humans: visual agnosia is typical for ventral damage, whereas optic ataxia (OA) for dorsal damage. We studied the case of a 59‐year‐old left‐handed woman with a circumscribed lesion around the left posterior occipital sulcus, extending to the underlying white matter. Initially, she presented with a central visual field OA, which regressed to an OA to the right visual hemifield during the 3 months observation period. In addition, tachistoscopic experiments showed visual hemiagnosia to the right visual hemifield. In line with the findings of the neuropsychological experiments, the analysis of the structural MR data by means of a trackwise hodologic probabilistic approach revealed damage to the left superior longitudinal fasciculus and to the left inferior longitudinal fasciculus, indicating an impairment of both the dorsal and the ventral stream. The combination of OA and visual hemiagnosia in the same patient has never been previously described. The present case study thus provides further insights for the understanding of visual processing.
Long‐term clinical and prosthetic outcomes of soft liner and clip attachments for bar/implant overdentures: a randomised controlled clinical trial
Authors: ELsyad M. A. , Shaheen N. H. , Ashmawy T. M.
Published: March 2017

Long‐term clinical and prosthetic outcomes of soft liner attachments for bar/implant overdentures were not sufficiently investigated. The aim of this trial was to evaluate clinical and prosthetic outcomes of resilient liner and clip attachments for bar/implant‐retained mandibular overdenture after 7 years. Thirty edentulous male participants received two implants in the canine areas of the mandible. Three months later, implants were splinted with a resilient bar. Mandibular overdentures were connected to the bars with either clip (CR group, n = 15) or resilient liner (RR group, n = 15) attachments. Plaque index (PI), gingival index (GI), probing depth (PD), vertical bone loss (VBL), horizontal bone loss (HBLO) and prosthetic complications (PCs) were evaluated at denture delivery (T0), 6 (T6m), 12 (T1), 24 (T2), 36 (T3), 48 (T4), 60 (T5), 72 (T6) and 84 (T7) months after insertion. PI and GI increased significantly with time for CR and decreased significantly for RR (P < 0·001). PD increased at T1 (CR) and T6 m (RR) and then decreased thereafter (P < 0·05). VBL increased significantly with time in both groups (P < 0·005). HBLO increased at T2 (CR) and T1 (RR) and then decreased thereafter. CR recorded significant higher PI, GI, PD, VBLO and HBLO compared to RR at all observation times (P < 0·042). The survival rates were 96·6% and 100% for CR and RR after 7 years. The most common PCs for CR and RR were clip wears and separation of the resilient liner from the denture base, respectively. Within the limitations of this study, resilient liner attachments are recommended for bar/implant‐retained mandibular overdentures than clip attachments in terms of peri‐implant tissue health and prosthetic complications after 7 years.
Realistic kinetic loading of the jaw system during single chewing cycles: a finite element study
Authors: Martinez Choy S. E. , Lenz J. , Schweizerhof K. , Schmitter M. , Schindler H. J.
Published: March 2017

Although knowledge of short‐range kinetic interactions between antagonistic teeth during mastication is of essential importance for ensuring interference‐free fixed dental reconstructions, little information is available. In this study, the forces on and displacements of the teeth during kinetic molar biting simulating the power stroke of a chewing cycle were investigated by use of a finite‐element model that included all the essential components of the human masticatory system, including an elastic food bolus. We hypothesised that the model can approximate the loading characteristics of the dentition found in previous experimental studies. The simulation was a transient analysis, that is, it considered the dynamic behaviour of the jaw. In particular, the reaction forces on the teeth and joints arose from contact, rather than nodal forces or constraints. To compute displacements of the teeth, the periodontal ligament (PDL) was modelled by use of an Ogden material model calibrated on the basis of results obtained in previous experiments. During the initial holding phase of the power stroke, bite forces were aligned with the roots of the molars until substantial deformation of the bolus occurred. The forces tilted the molars in the bucco‐lingual and mesio‐distal directions, but as the intrusive force increased the teeth returned to their initial configuration. The Ogden material model used for the PDL enabled accurate prediction of the displacements observed in experimental tests. In conclusion, the comprehensive kinetic finite element model reproduced the kinematic and loading characteristics of previous experimental investigations.
Codevelopment Between Key Personality Traits and Alcohol Use Disorder From Adolescence Through Young Adulthood
Authors: Samek Diana R. , Hicks Brian M. , Durbin Emily , Hinnant J. Benjamin , Iacono William G. , McGue Matthew
Published: March 2017

Objective

Personality traits related to negative emotionality and low constraint are strong correlates of alcohol use disorder (AUD), but few studies have evaluated the prospective interplay between these traits and AUD symptoms from adolescence to young adulthood.

Method

The Minnesota Twin Family Study (N = 2,769) was used to examine the developmental interplay between AUD symptoms and three personality measures of constraint, negative emotionality, and aggressive undercontrol from ages 17 to 29.

Results

Results from random‐intercept, cross‐lagged panel models showed that low constraint and aggressive undercontrol predicted subsequent rank‐order increases in AUD symptoms from ages 17 to 24. AUD symptoms did not predict rank‐order change in these traits from ages 17 to 24. There was support for both cross‐effects from ages 24 to 29. Biometric analysis of the twin data showed genetic influences accounted for most of the phenotypic correlations over time.

Conclusion

Results are consistent with the notion that personality traits related to low constraint and aggressive undercontrol are important vulnerability/predisposition factors for the development of early adult AUD. In later young adulthood, there is more evidence for the simultaneous codevelopment of personality and AUD. Implications are addressed with attention to personality‐based risk assessments and targeted AUD prevention approaches.
Think Positive? Examining the Impact of Optimism on Academic Achievement in Early Adolescents
Authors: Tetzner Julia , Becker Michael
Published: March 2017

Objective

Although optimism's beneficial role for various life areas is well documented, previous findings regarding its significance for students' achievement at school are inconclusive. This study examined the relation between optimism and academic achievement in early adolescents. It investigated the functional form of this relation, addressed whether the initial achievement level moderates this association, and compared this with effects on self‐esteem.

Method

We used a large German sample (N = 6,010; 53.2% females; baseline Mage = 14.1) with two measurement points over a period of 5 months (middle and end of 7th grade). Estimating LOESS curves and latent change‐regression models revealed three main findings.

Results

(a) Optimism showed a nonlinear association with subsequent changes in academic achievement: Optimism promoted academic achievement, but this positive association reached a plateau in above‐average optimism ranges and a minimum value in below‐average ranges of optimism. (b) The achievement level at t1 moderated this relation so that high optimism exerted a more positive effect for high‐achieving adolescents. (c) By contrast, optimism had an overall positive effect on self‐esteem.

Conclusions

The results therefore broaden the evidence on benefits of optimism by linking optimism to academic success in early adolescents but indicate only small and nonlinear associations.
Self‐Other Agreement and Metaperception Accuracy Across the Big Five: Examining the Roles of Depression and Self‐Esteem
Authors: Moritz Daniel , Roberts John E.
Published: March 2017

Objective

The ability to judge other people's personality characteristics and to know how we are viewed by others are important aspects of social cognition. The present study tested the impact of depressive symptoms and low self‐esteem on self‐other agreement and the accuracy of metaperception (i.e., how we believe others view us) across the Big Five dimensions of personality.

Method

Participants who varied in depressive symptoms engaged in a 10‐minute “getting to know you” interaction in dyads. Ratings on the Big Five personality dimensions, depression, and self‐esteem were completed prior to the interaction. After the interaction, participants rated the personality of their partner and rated how they believed their partner would rate them (metaperception).

Results

Self‐other agreement was only found on Extraversion, whereas there was significant meta‐accuracy on Agreeableness, Conscientiousness, and Extraversion. Depressive symptoms and low self‐esteem negatively biased metaperceptions of Agreeableness, Conscientiousness, and Neuroticism.

Conclusions

Depression and low self‐esteem function to negatively bias how we believe we are seen by others in new acquaintanceships and therefore may play an important role in the development of interpersonal relationships.
Biomineralization of calcium carbonate in the cell wall ofLithothamnion crispatum(Hapalidiales, Rhodophyta): correlation between the organic matrix and the mineral phase
Authors: de Carvalho Rodrigo Tomazetto , Salgado Leonardo Tavares , Amado Filho Gilberto Menezes , Leal Rachel Nunes , Werckmann Jacques , Rossi André Linhares , Campos Andrea Porto Carreiro , Karez Cláudia Santiago , Farina Marcos
Published: March 2017

Over the past few decades, progress has been made toward understanding the mechanisms of coralline algae mineralization. However, the relationship between the mineral phase and the organic matrix in coralline algae has not yet been thoroughly examined. The aim of this study was to describe the cell wall ultrastructure ofLithothamnion crispatum, a cosmopolitan rhodolith‐forming coralline algal species collected near Salvador (Brazil), and examine the relationship between the organic matrix and the nucleation and growth/shape modulation of calcium carbonate crystals. A nanostructured pattern was observed inL. crispatumalong the cell walls. At the nanoscale, the crystals fromL. crispatumconsisted of several single crystallites assembled and associated with organic material. The crystallites in the bulk of the cell wall had a high level of spatial organization. However, the crystals displayed cleavages in the (104) faces after ultrathin sectioning with a microtome. This organism is an important model for biomineralization studies as the crystallographic data do not fit in any of the general biomineralization processes described for other organisms. Biomineralization inL. crispatumis dependent on both the soluble and the insoluble organic matrix, which are involved in the control of mineral formation and organizational patterns through an organic matrix‐mediated process. This knowledge concerning the mineral composition and organizational patterns of crystals within the cell walls should be taken into account in future studies of changing ocean conditions as they represent important factors influencing the physico‐chemical interactions between rhodoliths and the environment in coralline reefs.
Rotala pseudojuniperina sp. nov. (Lythraceae) from India
Authors: Lekhak M. M. , Yadav S. R.
Published: March 2017

A new species, Rotala pseudojuniperina, is described and illustrated. It grows in a seasonal pond on a high altitude lateritic plateau ecosystem of the northern Western Ghats, India. It resembles the African species R. juniperina in having trimerous flowers, but differs in longer sepal appendages, ovoid capsule and ellipsoid seeds. Amongst the Indian species, R. pseudojuniperina shows affinities towards R. densiflora but differs in trimerous flowers, ovoid capsule and longer and ellipsoid seeds.
A novel GJA1 mutation in oculodentodigital dysplasia with extensive loss of enamel
Authors: Porntaveetus T , Srichomthong C , Ohazama A , Suphapeetiporn K , Shotelersuk V
Published: March 2017

Objective

To characterize clinical features and identify genetic causes of a patient with oculodentodigital dysplasia (ODDD).

Subjects and methods

Clinical, dental, radiological features were obtained. DNA was collected from an affected Thai family. Whole‐exome sequencing was employed to identify the disease‐causing mutation causing ODDD. The presence of the identified variant was confirmed by Sanger sequencing.

Results

The proband suffered with extensive enamel hypoplasia, polysyndactyly and clinodactyly of the 3rd–5th fingers, microphthalmia, and unique facial characteristics of ODDD. Mutation analysis revealed a novel missense mutation, c. 31C>A, p.L11I, in the GJA1 gene which encodes gap junction channel protein connexin 43. Bioinformatics and structural modeling suggested the mutation to be pathogenic. The parents did not harbor the mutation.

Conclusions

This study identified a novel de novo mutation in the GJA1 gene associated with severe tooth defects. These results expand the mutation spectrum and understanding of pathologic dental phenotypes related to ODDD.
A landscape of coexistence for a large predator in a human dominated landscape
Authors: Gehr Benedikt , Hofer Elizabeth J. , Muff Stefanie , Ryser Andreas , Vimercati Eric , Vogt Kristina , Keller Lukas F.
Published: March 2017

Human related mortality is a major threat for large carnivores all over the world and there is increasing evidence that large predators respond to human related risks in a similar way as prey respond to predation risk. This insight recently led to the conceptual development of a landscape of coexistence that can be used to identify areas which can sustain large predator populations in human dominated landscapes. In this study we applied the landscape of coexistence concept to a large predator in Europe. We investigated to what extent Eurasian lynx Lynx lynx habitat selection is affected by human disturbance in a human dominated landscape. More specifically, we were interested in the existence of a tradeoff between the availability of roe deer, one of their main prey and avoidance of human disturbance and how this affects the spatio‐temporal space use patterns of lynx. We found that lynx face a tradeoff between high prey availability and avoidance of human disturbance and that they respond to this by using areas of high prey availability (but also high human disturbance) during the night when human activity is low. Furthermore our analysis showed that lynx increase their travelling speed and remain more in cover when they are close to areas of high human disturbance. Despite clear behavioral adjustments in response to human presence, prey availability still proved to be the most important predictor of lynx occurrence at small spatial scale, whereas human disturbance was considerably less important. The results of our study demonstrate how spatio‐temporal adaptations in habitat selection enable large carnivores to persist in human dominated landscapes and demonstrate the usefulness of the concept of a landscape of coexistence to develop adaptive management plans for endangered populations of large carnivores.