bluuebunny/crossref_metadata_2025 huggingface dataset:
Visible and hidden sectors in a model with Maxwell and Chern–Simons gauge dynamics
Authors: Ireson Edwin , Schaposnik Fidel A. , Tallarita Gianni
Published: December 2016

We study a [Formula: see text] gauge theory discussing its vortex solutions and supersymmetric extension. In our set-up, the dynamics of one of two Abelian gauge fields is governed by a Maxwell term, the other by a Chern–Simons term. The two sectors interact via a BF gauge field mixing and a Higgs portal term that connects the two complex scalars. We also consider the supersymmetric version of this system which allows to find for the bosonic sector BPS equations in which an additional real scalar field enters into play. We study numerically the field equations finding vortex solutions with both magnetic flux and electric charge.
New acoustical technology of sound absorption based on reverse horn
Authors: Zhang Yong Yan , Wu Jiu Hui , Cao Song Hua , Cao Pei , Zhao Zi Ting
Published: December 2016

In this paper, a novel reverse horn’s sound-absorption mechanism and acoustic energy focusing mechanism for low-frequency broadband are presented. Due to the alternation of the reverse horn’s thickness, the amplitude of the acoustic pressure propagated in the structure changes, which results in growing energy focused in the edge and in the reverse horn’s tip when the characteristic length is equal to or less than a wavelength and the incident wave is compressed. There are two kinds of methods adopted to realize energy dissipation. On the one hand, sound-absorbing materials are added in incident direction in order to overcome the badness of the reverse horn’s absorption in high frequency and improve the overall high-frequency and low-frequency sound-absorption coefficients; on the other hand, adding mass and film in its tip could result in mechanical energy converting into heat energy due to the coupled vibration of mass and the film. Thus, the reverse horn with film in the tip could realize better sound absorption for low-frequency broadband. These excellent properties could have potential applications in the one-dimensional absorption wedge and for the control of acoustic wave.
Interactive visualization of 3d scanned mummies at public venues
Authors: Ynnerman Anders , Rydell Thomas , Antoine Daniel , Hughes David , Persson Anders , Ljung Patric
Published: December 2016

A full-body virtual autopsy of an ancient Egyptian mummy showed visitors he was likely murdered.
Industrial-scale agile
Authors: Jacobson Ivar , Spence Ian , Seidewitz Ed
Published: December 2016

Essence is instrumental in moving software development toward a true engineering discipline.
Threshold levels of extracellular l-arginine that trigger NOS-mediated ROS/RNS production in cardiac ventricular myocytes
Authors: Ramachandran Jayalakshmi , Peluffo R. Daniel
Published: December 2016

l-Arginine (L-Arg) is the substrate for nitric oxide synthase (NOS) to produce nitric oxide (NO), a signaling molecule that is key in cardiovascular physiology and pathology. In cardiac myocytes, L-Arg is incorporated from the circulation through the functioning of system-y+ cationic amino acid transporters. Depletion of L-Arg leads to NOS uncoupling, with O2 rather than L-Arg as the terminal electron acceptor, resulting in superoxide formation. The reactive oxygen species (ROS) superoxide (O2˙−), combined with NO, may lead to the production of the reactive nitrogen species (RNS) peroxynitrite (ONOO–), which is recognized as a major contributor to myocardial depression. In this study we aimed to determine the levels of external L-Arg that trigger ROS/RNS production in cardiac myocytes. To this goal, we used a two-step experimental design in which acutely isolated cardiomyocytes were loaded with the dye coelenterazine that greatly increases its fluorescence quantum yield in the presence of ONOO– and O2˙−. Cells were then exposed to different concentrations of extracellular L-Arg and changes in fluorescence were followed spectrofluorometrically. It was found that below a threshold value of ~100 µM, decreasing concentrations of L-Arg progressively increased ONOO–/ O2˙−-induced fluorescence, an effect that was not mimicked by d-arginine or l-lysine and was fully blocked by the NOS inhibitor l-NAME. These results can be explained by NOS aberrant enzymatic activity and provide an estimate for the levels of circulating L-Arg below which ROS/RNS-mediated harmful effects arise in cardiac muscle.
Vascular function and endothelin-1: tipping the balance between vasodilation and vasoconstriction
Authors: Nishiyama Steven K. , Zhao Jia , Wray D. Walter , Richardson Russell S.
Published: December 2016

Endothelin-1 (ET-1), a potent vasoconstrictor secreted by vascular endothelial cells, has been implicated in the pathophysiology of numerous cardiovascular diseases, yet the direct impact of ET-1 on vascular function remains unclear. Therefore, in seven young (23 ± 1 yr) healthy subjects, we investigated the effect of an intra-arterial infusion of ET-1 on reactive hyperemia (RH) and flow-mediated dilation (FMD) in the popliteal artery following 5 min of suprasystolic cuff occlusion. ET-1 infusion significantly attenuated basal leg blood flow (control: 62 ± 4 ml/min, ET-1: 47 ± 9 ml/min), RH [area-under-curve (AUC); control: 162 ± 15 ml, ET-1: 104 ± 16 ml], and peak RH (control: 572 ± 51 ml/min, ET-1: 412 ± 32 ml/min) ( P < 0.05). Administration of ET-1 also reduced FMD (control: 2.4 ± 0.3%, ET-1: 0.5 ± 0.5%) and FMD normalized for shear rate (control: 10.5 × 10−4 ± 2.0 × 10−4%/s−1, ET-1: 0.9 × 10−4 ± 2.8 ×10−4%/s−1). These findings reveal that elevated levels of ET-1 have a significant impact on vascular function, indicating that studies employing RH and FMD as markers of microvascular function and nitric oxide bioavailability, respectively, should exercise caution, as ET-1 can impact these assessments by tipping the balance between vasodilation and vasoconstriction, in favor of the latter.

NEW & NOTEWORTHY Endothelin-1 (ET-1) is recognized as the body’s most potent endogenous vasoconstrictor, but the impact of this peptide on vascular function is not well understood. The present study revealed that the intra-arterial administration of ET-1 impaired both microvascular and conduit vessel function of the leg in young, healthy, humans. Studies employing vascular testing in patient cohorts that experience a disease-related increase in ET-1 should thus exercise caution, as ET-1 clearly impairs vascular function.
CORP: Minimizing the chances of false positives and false negatives
Authors: Curran-Everett Douglas
Published: December 2016

Statistics is essential to the process of scientific discovery. An inescapable tenet of statistics, however, is the notion of uncertainty which has reared its head within the arena of reproducibility of research. The Journal of Applied Physiology’s recent initiative, “Cores of Reproducibility in Physiology,” is designed to improve the reproducibility of research: each article is designed to elucidate the principles and nuances of using some piece of scientific equipment or some experimental technique so that other researchers can obtain reproducible results. But other researchers can use some piece of equipment or some technique with expert skill and still fail to replicate an experimental result if they neglect to consider the fundamental concepts of statistics of hypothesis testing and estimation and their inescapable connection to the reproducibility of research. If we want to improve the reproducibility of our research, then we want to minimize the chance that we get a false positive and—at the same time—we want to minimize the chance that we get a false negative. In this review I outline strategies to accomplish each of these things. These strategies are related intimately to fundamental concepts of statistics and the inherent uncertainty embedded in them.
Statistical Analyses of Femur Parameters for Designing Anatomical Plates
Authors: Wang Lin , He Kunjin , Chen Zhengming
Published: December 2016

Femur parameters are key prerequisites for scientifically designing anatomical plates. Meanwhile, individual differences in femurs present a challenge to design well-fitting anatomical plates. Therefore, to design anatomical plates more scientifically, analyses of femur parameters with statistical methods were performed in this study. The specific steps were as follows. First, taking eight anatomical femur parameters as variables, 100 femur samples were classified into three classes with factor analysis and Q-type cluster analysis. Second, based on the mean parameter values of the three classes of femurs, three sizes of average anatomical plates corresponding to the three classes of femurs were designed. Finally, based on Bayes discriminant analysis, a new femur could be assigned to the proper class. Thereafter, the average anatomical plate suitable for that new femur was selected from the three available sizes of plates. Experimental results showed that the classification of femurs was quite reasonable based on the anatomical aspects of the femurs. For instance, three sizes of condylar buttress plates were designed. Meanwhile, 20 new femurs are judged to which classes the femurs belong. Thereafter, suitable condylar buttress plates were determined and selected.
Simultaneous Combined Myositis, Inflammatory Polyneuropathy, and Overlap Myasthenic Syndrome
Authors: Mathis Stéphane , Magy Laurent , Corcia Philippe , Ghorab Karima , Richard Laurence , Ciron Jonathan , Duchesne Mathilde , Vallat Jean-Michel
Published: December 2016

Immune-mediated neuromuscular disorders include pathologies of the peripheral nervous system, neuromuscular junction, and muscles. If overlap syndromes (or the association of almost two autoimmune disorders) are recognized, the simultaneous occurrence of several autoimmune neuromuscular disorders is rare. We describe two patients presenting the simultaneous occurrence of inflammatory neuropathy, myositis, and myasthenia gravis (with positive acetylcholine receptor antibodies). For each patient, we carried out a pathological analysis (nerve and muscle) and an electrophysiological study (and follow-up). To our knowledge, this is the first description of such a triple immune-mediated neuromuscular syndrome. We compared our observations with a few other cases of simultaneous diagnosis of two inflammatory neuromuscular disorders.
Polymer Electrolyte Membrane Fuel Cell Performance of a Sulfonated Poly(Arylene Ether Benzimidazole) Copolymer Membrane
Authors: Gerçel Hasan Ferdi , Tosun Çağla Gül , Akyalçın Levent
Published: December 2016

Disodium-3,3′-disulfonate-4,4′-dichlorodiphenylsulfone (SDCDPS) and 5,5′-bis[2-(4-hydroxyphenyl)benzimidazole] (HPBI) monomers were synthesized. Binding these monomers via nucleophilic aromatic polycondensation reaction, a sulfonated poly(arylene ether benzimidazole) copolymer was synthesized. Structures of monomers and copolymer were confirmed by proton nuclear magnetic resonance spectroscopy (1H NMR) and Fourier transform infrared (FTIR) spectroscopy analyses. Proton exchange membrane was prepared by dissolving copolymer in dimethylacetamide (DMAc) and casting onto a glass plate. Copolymer membrane was doped with sulfuric acid to ensure proton exchange character. Single cell performance of the copolymer membrane was tested in a polymer electrolyte membrane fuel cell test station. The highest power density of the membrane was measured as 23.7 mW cm−2 at 80°C. Thermogravimetric analysis (TGA) showed that as the degree of disulfonation is increased thermal stability of the copolymer is increased.
Stimulator Selection in SSVEP-Based Spatial Selective Attention Study
Authors: Xie Songyun , Liu Chang , Obermayer Klaus , Zhu Fangshi , Wang Linan , Xie Xinzhou , Wang Wei
Published: December 2016

Steady-State Visual Evoked Potentials (SSVEPs) are widely used in spatial selective attention. In this process the two kinds of visual simulators, Light Emitting Diode (LED) and Liquid Crystal Display (LCD), are commonly used to evoke SSVEP. In this paper, the differences of SSVEP caused by these two stimulators in the study of spatial selective attention were investigated. Results indicated that LED could stimulate strong SSVEP component on occipital lobe, and the frequency of evoked SSVEP had high precision and wide range as compared to LCD. Moreover a significant difference between noticed and unnoticed frequencies in spectrum was observed whereas in LCD mode this difference was limited and selectable frequencies were also limited. Our experimental finding suggested that average classification accuracies among all the test subjects in our experiments were 0.938 and 0.853 in LED and LCD mode, respectively. These results indicate that LED simulator is appropriate for evoking the SSVEP for the study of spatial selective attention.
Determination of Spatial Chromium Contamination of the Environment around Industrial Zones
Authors: Homa Dereje , Haile Ermias , Washe Alemayehu P.
Published: December 2016

This study was conducted to determine the spatial levels of chromium contamination of water, agricultural soil, and vegetables in the leather tanning industrial areas using spectrophotometric methods. The results showed elevated accumulation of total Cr ranging from10.85±0.885 mg/L to39.696±0.326 mg/L,16.225±0.12 mg/Kg to1581.667±0.122 mg/Kg, and1.0758±0.05348 mg/Kg to11.75±0.206 mg/Kg in water, agricultural soil, and vegetable samples, respectively. The highest levels of chromium (VI) found from the speciation study were2.23±0.032 mg/Kg and0.322±0.07 mg/L in soil and water samples, respectively, which decreased with distance from the tannery. Among the vegetables, the highest load of Cr(VI) was detected in onion root (0.048±0.065 mg/Kg) and the lowest (0.004±0.007 mg/Kg) in fruit of green pepper. The detected levels of Cr in all of the suggested samples were above the WHO permissible limits. The variations of the levels Cr(III) and Cr(VI) contamination of the environment with distance from the tannery were statistically significant (p=0.05). Similarly, significant difference in the levels of Cr among the tested vegetables was recorded. The levels increased with decreasing distance from the effluent channel.
Radiofrequency Ablation-Assisted Zero-Ischemia Robotic Laparoscopic Partial Nephrectomy: Oncologic and Functional Outcomes in 49 Patients
Authors: Rimar Kalen , Khambati Aziz , McGuire Barry B. , Rebuck David A. , Perry Kent T. , Nadler Robert B.
Published: December 2016

Introduction and Objectives. Robotic partial nephrectomy with peritumoral radiofrequency ablation (RFA-RPN) is a novel clampless technique. We describe oncologic and functional outcomes in a prospective cohort. Methods. From May, 2007, to December, 2009, 49 consecutive patients with renal masses <7 cm underwent RFA-RPN. During this period, only the RFA-RPN technique was utilized for all cases of partial nephrectomy. Pre- and postoperative data were analyzed and compared to 36 consecutive patients who underwent LPN. Results. In total, 49 tumors were treated in the RFA-RPN group and 36 tumors in the comparison group. Mean operative time was longer in the RFA-RPN group (370 min versus 293 min, p<0.001). There were no significant differences in mean EBL (231 cc versus 250 cc, p=0.42), transfusion rate (8.2% versus 11.1%, p=0.7), or hospital stay (3.9 versus 4.4 days, p=0.2). Two patients in the RFA-RPN (4.1%) and 1 (2.7%) patient in the comparison group had a positive surgical margin (p=0.75). 17 (34.7%) patients had a postoperative urine leak in the RFA-RPN group versus 2 (5.6%) patients in the comparison group (p=0.001). Mean follow-up was 54 months versus 68.4 months in the comparison group. There was no significant difference between the two groups regarding change in GFR (p=0.67). There were 3 recurrences (6.1%) in the RFA-RPN group and 0 recurrences in the RPN group (p=0.23). There were 3 deaths (6.1%) in the RFA-RPN group (one cancer specific) and 4 deaths (11.1%) in the RPN group (non-cancer specific) over the follow-up period (p=0.44). Conclusions. Our data suggests that this technique is associated with a similar degree of renal preservation but higher rates of postoperative urine leak and possibly higher rates of recurrence.
Common Adverse Effects of Anti-TNF Agents on Gestation
Authors: Fasoulakis Zacharias , Antsaklis Panagiotis , Galanopoulos Nikolaos , Kontomanolis Emmanuel
Published: December 2016

Autoimmune disease has affected up to 50 million Americans, according to the American Autoimmune Related Diseases Association (AARDA) and 75 percent of those affected are women. These inflammatory diseases have variable activity and a lot of women will have to undergo major therapies during and after pregnancy. Many of the women suffering from these disease will improve during gestation. However a lot of women will require continuation of disease-modifying therapies (i.e., biological therapies) throughout pregnancy and post-partum involving many risks. In the past decade all gaze turned to biological therapies, as an attempt, to obtain even more effective medications in order to suppress the exacerbation of autoimmune disease, even at the most unfit circumstances such as pregnancy. The results are both satisfying and promising since increasingly proven thoughts prevail on making anti-TNF agents first-line medications, clearing up the limited knowledge over human influence. The purpose of this review is to summarize the results of the reports with the highest and representative range of patients of the last decade involving the use of anti-TNF agents during pregnancy.
Protease Inhibitors Extracted fromCaesalpinia echinataLam. Affect Kinin Release during Lung Inflammation
Authors: Cruz-Silva Ilana , Nunes Viviane Abreu , Gozzo Andrezza Justino , Praxedes-Garcia Priscila , Tanaka Aparecida Sadae , Shimamoto Kazuaki , Araujo Mariana Silva
Published: December 2016

Inflammation is an essential process in many pulmonary diseases in which kinins are generated by protease action on kininogen, a phenomenon that is blocked by protease inhibitors. We evaluated kinin release in anin vivolung inflammation model in rats, in the presence or absence of CeKI (C. echinatakallikrein inhibitor), a plasma kallikrein, cathepsin G, and proteinase-3 inhibitor, and rCeEI (recombinantC. echinataelastase inhibitor), which inhibits these proteases and also neutrophil elastase. Wistar rats were intravenously treated with buffer (negative control) or inhibitors and, subsequently, lipopolysaccharide was injected into their lungs. Blood, bronchoalveolar lavage fluid (BALF), and lung tissue were collected. In plasma, kinin release was higher in the LPS-treated animals in comparison to CeKI or rCeEI groups. rCeEI-treated animals presented less kinin than CeKI-treated group. Our data suggest that kinins play a pivotal role in lung inflammation and may be generated by different enzymes; however, neutrophil elastase seems to be the most important in the lung tissue context. These results open perspectives for a better understanding of biological process where neutrophil enzymes participate and indicate these plant inhibitors and their recombinant correlates for therapeutic trials involving pulmonary diseases.
Miniaturized Digestion and Extraction of Surface Proteins fromCandida albicansfollowing Treatment with Histatin 5 for Mass Spectrometry Analysis
Authors: Fan Shirley , Moffa Eduardo B. , Xiao Yizhi , Siqueira Walter L. , Yeung Ken K.-C.
Published: December 2016

A common approach to isolate surface proteins from fungal and bacterial cells is to perform a proteolytic cleavage of proteins on the surface of intact cells suspended in solution. This paper describes miniaturization of this technique, in which cells are adhered on glass surfaces, and all sample treatments are conducted atμL volumes. Specifically,Candida albicanscells were attached onto HSA-coated glass slides. By depositing the appropriate reagent solutions on the adhered cells, we successfully performed cell washing, treatment with antifugal peptide, Histatin 5, and a proteolysis on intact cells with trypsin. The resulting peptides were subsequently analysed by mass spectrometry. In general, the data obtained was similar to that collected with suspended cells in much larger sample volumes. However, our miniaturized workflow offers the benefit of greatly reducing the consumption of cells and reagents.
A PAM50-Based Chemoendocrine Score for Hormone Receptor–Positive Breast Cancer with an Intermediate Risk of Relapse
Authors: Prat Aleix , Lluch Ana , Turnbull Arran K. , Dunbier Anita K. , Calvo Lourdes , Albanell Joan , de la Haba-Rodríguez Juan , Arcusa Angels , Chacón José Ignacio , Sánchez-Rovira Pedro , Plazaola Arrate , Muñoz Montserrat , Paré Laia , Parker Joel S. , Ribelles Nuria , Jimenez Begoña , Bin Aiderus Abdul Aziz , Caballero Rosalía , Adamo Barbara , Dowsett Mitch , Carrasco Eva , Martín Miguel , Dixon J. Michael , Perou Charles M. , Alba Emilio
Published: December 2016

Purpose: Hormone receptor–positive (HR+) breast cancer is clinically and biologically heterogeneous, and subgroups with different prognostic and treatment sensitivities need to be identified.

Experimental Design: Research-based PAM50 subtyping and expression of additional genes was performed on 63 patients with HR+/HER2− disease randomly assigned to neoadjuvant multiagent chemotherapy versus endocrine therapy in a phase II trial. The biology associated with treatment response was used to derive a PAM50-based chemoendocrine score (CES). CES's predictive ability was evaluated in 4 independent neoadjuvant data sets (n = 675) and 4 adjuvant data sets (n = 1,505). The association of CES, intrinsic biology, and PAM50 risk of relapse (ROR) was explored across 6,007 tumors.

Results: Most genes associated with endocrine sensitivity were also found associated with chemotherapy resistance. In the chemotherapy test/validation data sets, CES was independently associated with pathologic complete response (pCR), even after adjusting for intrinsic subtype. pCR rates of the CES endocrine–sensitive (CES-E), uncertain (CES-U), and chemotherapy-sensitive (CES-C) groups in both data sets combined were 25%, 11%, and 2%, respectively. In the endocrine test/validation data sets, CES was independently associated with response. Compared with ROR, >90% of ROR-low and ROR-high tumors were identified as CES-E and CES-C, respectively; however, each CES group represented >25% of ROR-intermediate disease. In terms of survival outcome, CES-C was associated with poor relapse-free survival in patients with ROR-intermediate disease treated with either adjuvant endocrine therapy only or no adjuvant systemic therapy, but not in patients treated with (neo)adjuvant chemotherapy.

Conclusions: CES is a genomic signature capable of estimating chemoendocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse. Clin Cancer Res; 23(12); 3035–44. ©2016 AACR.
Astrocyte Elevated Gene-1 Regulates β-Catenin Signaling to Maintain Glioma Stem-like Stemness and Self-Renewal
Authors: Hu Bin , Emdad Luni , Kegelman Timothy P. , Shen Xue-Ning , Das Swadesh K. , Sarkar Devanand , Fisher Paul B.
Published: December 2016

Glioblastoma multiforme is a common malignant brain tumor that portends extremely poor patient survival. Recent studies reveal that glioma stem-like cells (GSC) are responsible for glioblastoma multiforme escape from chemo-radiotherapy and mediators of tumor relapse. Previous studies suggest that AEG-1 (MTDH), an oncogene upregulated in most types of cancers, including glioblastoma multiforme, plays a focal role linking multiple signaling pathways in tumorigenesis. We now report a crucial role of AEG-1 in glioma stem cell biology. Primary glioblastoma multiforme cells were isolated from tumor specimens and cultured as neurospheres. Using the surface marker CD133, negative and positive cells were separated as nonstem and stem populations by cell sorting. Tissue samples and low passage cells were characterized and compared with normal controls. Functional biological assays were performed to measure stemness, self-renewal, differentiation, adhesion, protein–protein interactions, and cell signaling. AEG-1 was upregulated in all glioblastoma multiforme neurospheres compared with normal neural stem cells. Expression of AEG-1 was strongly associated with stem cell markers CD133 and SOX2. AEG-1 facilitated β-catenin translocation into the nucleus by forming a complex with LEF1 and β-catenin, subsequently activating Wnt signaling downstream genes. Through an AEG-1/Akt/GSK3β signaling axis, AEG-1 controlled phosphorylation levels of β-catenin that stabilized the protein.

Implications: This study discovers a previously unrecognized role of AEG-1 in GSC biology and supports the significance of this gene as a potential therapeutic target for glioblastoma multiforme. Mol Cancer Res; 15(2); 225–33. ©2016 AACR.
Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations
Authors: Shin Daniel Sanghoon , Zaretsky Jesse M. , Escuin-Ordinas Helena , Garcia-Diaz Angel , Hu-Lieskovan Siwen , Kalbasi Anusha , Grasso Catherine S. , Hugo Willy , Sandoval Salemiz , Torrejon Davis Y. , Palaskas Nicolaos , Rodriguez Gabriel Abril , Parisi Giulia , Azhdam Ariel , Chmielowski Bartosz , Cherry Grace , Seja Elizabeth , Berent-Maoz Beata , Shintaku I. Peter , Le Dung T. , Pardoll Drew M. , Diaz Luis A. , Tumeh Paul C. , Graeber Thomas G. , Lo Roger S. , Comin-Anduix Begoña , Ribas Antoni
Published: December 2016

Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti–PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair–deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti–PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to a lack of PD-L1 expression upon interferon gamma exposure mediated by an inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in The Cancer Genome Atlas confer adverse outcomes in patients. We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.

Significance: A key functional result from somatic JAK1/2 mutations in a cancer cell is the inability to respond to interferon gamma by expressing PD-L1 and many other interferon-stimulated genes. These mutations result in a genetic mechanism for the absence of reactive PD-L1 expression, and patients harboring such tumors would be unlikely to respond to PD-1 blockade therapy. Cancer Discov; 7(2); 188–201. ©2016 AACR.

See related commentary by Marabelle et al., p. 128.

This article is highlighted in the In This Issue feature, p. 115
Translating Science into Survival: Report on the Second International Cancer Immunotherapy Conference
Authors: Brodsky Arthur N. , Hubbard-Lucey Vanessa M.
Published: December 2016

On September 25–28, 2016, in New York City, the Second International Cancer Immunotherapy Conference was cohosted by the Cancer Research Institute, the American Association for Cancer Research, the Association for Cancer Immunotherapy, and the European Academy of Tumor Immunology. This exciting conference brought together more than 1,400 participants, including scientists, clinicians, investors, and regulators, to discuss the latest scientific advances within the field of cancer immunotherapy. This conference report reviews the chief themes that emerged during the 4-day meeting. Cancer Immunol Res; 4(12); 996–1000. ©2016 AACR.
A Case of Proliferative Retinopathy Complicated with Tuberous Sclerosis Treated by Vitreous Surgery
Authors: Nemoto Emika , Morishita Seita , Akashi Mari , Kohmoto Ryohsuke , Fukumoto Masanori , Suzuki Hiroyuki , Kobayashi Takatoshi , Kida Teruyo , Sugasawa Jun , Ikeda Tsunehiko
Published: December 2016

We report a case of proliferative retinopathy complicated with retinal hamartoma in a tuberous sclerosis patient. This study involved a 16-year-old female patient who was diagnosed as having tuberous sclerosis at birth. Ophthalmic examination revealed retinal hamartoma surrounding the optic disc in both eyes. Vitreous surgery involving a vitrectomy and resection of the proliferative membranes was performed for proliferative retinopathy in her right eye. Postoperative fundus findings showed improvement and decreased exudative changes. The proliferative and exudative changes appeared to be due to the retinal hamartoma, and vitreous surgery proved effective in this case.
Idarucizumab does not have procoagulant effects: Assessment of thrombosis biomarkers in healthy volunteers
Authors: Schmohl Michael , Glund Stephan , Harada Akiko , Imazu Susumu , Smet Marina De , Moschetti Viktoria , Ramael Steven , Ikushima Ippei , Grünenfelder Fredrik , Reilly Paul , Stangier Joachim
Published: December 2016

Idarucizumab, a humanised monoclonal antibody fragment, binds dabigatran with high affinity and immediately, completely and sustainably reverses dabigatran-induced changes on blood coagulation. The present analysis focuses on the evaluation of potential procoagulant properties of idarucizumab when administered in the absence of dabigatran. As part of two Phase I studies conducted in healthy Caucasian and Japanese male volunteers, the effect of idarucizumab (8 g as a 1-hour [h] infusion and 4 g as a 5-minute [min] infusion) and placebo on calibrated automated thrombography (CAT) was assessed using platelet-poor plasma samples. Measures were made before and 15 min after the end of infusion in Caucasian subjects, as well as predose, 15 min, 4 h and 8 h in Japanese subjects. The levels of the thrombosis markers D-dimer and prothrombin fragment 1 + 2 (F1.2) were assessed over time in plasma samples up to 72 h after the end of infusion of idarucizumab and placebo. Idarucizumab had no apparent effect on endogenous thrombin formation as measured by CAT. D-dimer and F1.2 levels were highly variable in all dose groups but did not increase when compared with placebo or pre-dose levels. In conclusion, idarucizumab had no effect on endogenous thrombin generation. Additional markers of thrombosis, F1.2 and D-dimer, did not differ between placebo and idarucizumab, indicating a lack of procoagulant properties of idarucizumab.
Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A
Authors: Giangrande Paul , Andreeva Tatiana , Chowdary Pratima , Ehrenforth Silke , Hanabusa Hideji , Leebeek Frank W. G. , Lentz Steven R. , Nemes Laszlo , Poulsen Lone Hvitfeldt , Santagostino Elena , You Chur Woo , Ong Clausen Wan Hui , Jönsson Peter G. , Oldenburg Johannes ,   for the Pathfinder™2 Investigators
Published: December 2016

Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20–75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00–4.61), the mean ABR was 3.70 (95 % confidence interval 2.94–4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.
Discovery and Validation of Agonistic Angiotensin Receptor Autoantibodies as Biomarkers of Adverse Outcomes
Authors: Abadir Peter M. , Jain Alka , Powell Laura J. , Xue Qian-Li , Tian Jing , Hamilton Robert G. , Bennett David A. , Finucane Thomas , Walston Jeremy D. , Fedarko Neal S.
Published: December 2016

Background:

Agonistic angiotensin II type 1 receptor autoantibodies (AT1RaAbs) have not been associated with functional measures or risk for adverse health outcomes. AT1RaAbs could be used to stratify patient risk and to identify patients who can benefit from angiotensin receptor blocker treatment.

Methods:

Demographic and physiological covariates were measured in a discovery set of community-dwelling adults from Baltimore (N=255) and AT1RaAb associations with physical function tests and outcomes assessed. A group from Chicago (N=60) was used for validation of associations and to explore the impact of angiotensin receptor blocker treatment.

Results:

The Baltimore group had 28 subjects with falls, 32 frail subjects, and 5 deaths. Higher AT1RaAbs correlated significantly with interleukin-6 (Spearman
r
=0.33,
P
<0.0001), systolic blood pressure (Spearman
r
=0.28,
P
<0.0001), body mass index (Spearman
r
=0.28,
P
<0.0001), weaker grip strength (Spearman
r
=–0.34,
P
<0.01), and slower walking speed (Spearman
r
=–0.30,
P
<0.05). Individuals with high AT1RaAbs were 3.9 (95% confidence interval, 1.38–11.0) times more likely to be at high risk after adjusting for age (
P
<0.05). Every 1 µg/mL increase in AT1RaAbs increased the odds of falling 30% after adjusting for age, sex, body mass index, and blood pressure. The Chicago group had 46 subjects with falls and 60 deaths. Serum AT1RaAb levels were significantly correlated with grip strength (Spearman
r
=–0.57,
P
<0.005), walking speed (Spearman
r
=–0.47,
P
<0.005), and falls (Spearman
r
=0.30,
P
<0.05). Every 1 µg/mL increase in AT1RaAbs, decreased time to death by 9% after adjusting for age, sex, body mass index, and blood pressure. Chronic treatment with angiotensin receptor blockers was associated with better control of systolic blood pressure and attenuation of decline in both grip strength and time to death.

Conclusions:

In older individuals, higher AT1RaAb levels were associated with inflammation, hypertension, and adverse outcomes. Angiotensin receptor blocker treatment may blunt the harm associated with high levels of AT1RaAb.
Kuyper’s Common Grace and Kelsey
Authors: Stubbs David L.
Published: December 2016

“Common grace” has played an important but disputed role in the Reformed tradition’s picture of God’s relationship to the creation. While providing a theological foundation for many Calvinists’ cultural engagement, certain ambiguities and issues plague the concept. By comparing it to another Reformed vision of God’s continuing creative relationship to the creation, namely that of David Kelsey in his book titled Eccentric Existence, and examining especially three aspects of Kelsey’s vision—i.e. the distinctions between God’s operations, the Trinitarian underpinnings of God’s creational activity, and the proper human response to that activity—promising directions for the common grace tradition are highlighted.
Coffeehouses, Urban Spaces, and the Formation of a Public Sphere in Safavid Isfahan
Authors: Emami Farshid
Published: December 2016

This essay examines the urban topography, physical structure, and social context of coffeehouses in Safavid Iran (1501–1722), particularly in the capital city of Isfahan. Through a reconstruction of the architecture and urban configuration of coffeehouses, the essay shows how, as an utterly novel institution, the coffeehouse opened up a new sphere of public life, engendered new conceptions of urbanity, and altered the social meaning of urban spaces. The essay will specifically focus on the drinking houses that existed in the Maydan-i Naqsh-i Jahan and Khiyaban-i Chaharbagh, the grand urban spaces of seventeenth-century Isfahan. The remaining physical traces, together with textual and visual evidence, permit us to reconstruct Isfahan’s major coffeehouses. This analysis not only reveals a less-appreciated aspect of urbanity in the age of Shah ʿAbbas (r. 1587–1629) but also elucidates the ways in which the public spaces of Safavid Isfahan contained and shaped novel social practices particular to the early modern age.
Envisioning the Orient: The New Muslim Cemetery in Malta
Authors: Thake Conrad
Published: December 2016

This paper analyzes a project for a new Muslim cemetery in Malta that was realized in 1873–74. It investigates the process of commissioning and implementing the project through an intricate set of relationships between the colonial authorities in Malta, then a British island-colony in the Mediterranean, and the Ottoman, Tunisian, and Moroccan authorities. It considers the key roles played by the various institutional agents and protagonists involved in conceptualizing and executing the project, from the Ottoman sultan Abdülaziz I, acting through his political and cultural interlocutor, the Ottoman consul Naoum Duhany, to Emanuele Luigi Galizia, the Maltese architect who designed the cemetery, and the British colonial authorities who permitted its construction. This paper also explores issues relating to the forms of neo-Ottoman architectural representation during the late nineteenth century, as it was actively promoted within a Western European cultural context and, in this case, on the peripheral edge, far removed from the traditional cosmopolitan urban centers. The Ottoman patronage of an overtly exotic and Orientalist building complex, “exported” to a British colonial outpost in the Mediterranean, gives rise to a series of political and ideological issues. This case study serves to provide broader and revisionary insights into the current discourse on Orientalism, not as a closed and binary system but rather as an open-ended and flexible form of artistic representation.
Investors’ Remedies under EU Law and International Investment Law
Authors: Paparinskis Martins
Published: December 2016

Legal orders of international investment law and European Union law both provide remedies for investors. This article does not consider whether these remedies are available to the same actors in relation to the same conduct. The argument is limited to comparison of remedies under investment law, almost exclusively compensatory in character and implemented through investor-State arbitration, with remedies under EU law, particularly State liability claims in domestic courts. This comparison at the level of legal principle is not nonsensical – concepts of attribution, breach, rights, and causality do evoke somewhat similar considerations – but ultimately the extent of systemic differences as well as lack of information about crucial aspects of remedies make these matters incommensurable. It is not obvious that comparison of experience of States that have been addressees of both kinds of remedies is more illuminating than the comparison of principle.
Rebalancing Investment Treaties and Investor-State Arbitration: Two Approaches
Authors: Nottage Luke
Published: December 2016

This essay reviews two books suggesting how international investment law may be recalibrated to balance the interests of foreign investors and host states. Poulsen’s book draws mainly on empirical research to argue that developing states displayed ‘bounded rationality’ when rushing to sign up to investment treaties incorporating pro-investor protections, such investor-state arbitration. Although mainly descriptive, it sketches potential reforms of the investment treaty system to achieve a more rational balance in favour of host states. By contrast, drawing on doctrinal analysis but with a keen awareness of the institutional underpinnings of international investment law and arguably analogous fields, the book by Henckels focuses on what arbitrators and commentators can do to extend a tendency to interpret substantive protections even within existing investment treaties in a more balanced way. She urges more consistent application of multi-layered ‘proportionality’ analysis, combined with principled ‘deference’ to regulatory decision-making by host states.
Shading and the Landmarks of Relief
Authors: Koenderink Jan , van Doorn Andrea , Wagemans Johan , Pinna Baingio
Published: December 2016

Shading is a visual artist’s tool. It enables the indication of ‘landmarks’ inside the outline of shapes. Shading triggers behavioral responses in organisms throughout the animal kingdom and even affects the habitus of plants. Radiometry might be expected to account for the phenomenology. We derive the formal structures of shading that are expected to play a dominant role in perception. That they fail to do so suggests that shading is more of an interface template than a ‘cue’. This fits the artistic use as a ‘releaser’ very well. Pre-modern artists hardly acknowledge causal relations between various photometric variables. Their works show an effective use of various elements in their own right, without attempts at causal congruity. Modern art often defies physics on purpose. We identify manifest templates and relate these to conventional techniques in the visual arts.
School libraries, political information and information literacy provision:
Authors: Smith Lauren
Published: December 2016

This paper presents the findings of research which explored Scottish school libraries’ information provision and information literacy (IL) support in the run-up to two major political events: the 2014 Scottish Independence Referendum (SIR) and the 2015 General UK Parliamentary Election (GE). To do this, the project identified, through an online survey, what political information seeking secondary school students engaged in through school libraries, what information provision and IL support was available to students relating to political issues and events, and what barriers school libraries faced in providing these aspects of political education. It also identified what information seeking students engaged in, what levels of information provision and IL support relating to politics are provided by school libraries, and to explore the perceptions and experiences of library staff relating to work in this area. Analysis of the results indicates that there are mixed levels of provision across school libraries in Scotland and that this variation may be influenced by inconsistent policies from local councils and individual schools themselves, as well as variations in the experience and views of library staff. Key activities to support young people’s political education are identified, and several reasons library staff do not engage in political work are discussed. The findings are linked to previous research, with a discussion of the need to encourage and support school library staff to contribute to the political education of students alongside teaching staff. Several recommendations for schools and library staff are made, relating to a consideration of the role of school libraries, how they can provide relevant political information, the importance of clear policies around political information provision and the support required for school library workers.
Lost and found: the Plecoptera types of Blanchard and Mabille, with further contributions to the stoneflies of Chile
Authors: MURÁNYI DÁVID , GAMBOA MARIBET , VERA ALEJANDRO
Published: December 2016

Types of five of the six Plecoptera species described by Émile Blanchard and the holotype of the single stonefly described by Jules François Mabille were discovered in the National Museum Prague, Czech Republic. The identity of P. myrmidon Mabille, 1891 and P. pictetii Blanchard, 1854 are confirmed as Potamoperla myrmidon and Pictetoperla gayi (Pictet, 1841), respectively. Perla virescentipennis Blanchard, 1851 is considered as Diamphipnopsis virescentipennis comb. n., with Diamphipnosis samali Illies, 1960 syn. n. as a junior subjective synonym, and Diamphipnoa chillanae nom. n. is proposed for D. virescentipennis sensu Illies 1960. Lectotypes are designated for three species: Nemoura rufescens Blanchard, 1851 is redescribed as Austronemoura rufescens (Blanchard, 1851) comb. n., with Perla infuscata Blanchard, 1851 syn. n. and Perla blanchardi Jakobson & Bianchi, 1905 syn. n. designated as junior subjective synonyms, whereas Perla stictica Blanchard, 1851 is treated as Neonemura stictica (Blanchard, 1851) comb. n., nomen dubium. Paralectotypes of these three species belong to further four taxa. Due to the missing syntypes, Perla lineatocollis Blanchard, 1851 is treated as a nomen dubium of uncertain suborder assignment. Specimens of the Blanchard collections that cannot regarded as types are enumerated belonging to six species. Recent collections of 15 species from Chile are also reported.
Do Highly Paid, Highly Skilled Women Experience the Largest Motherhood Penalty?
Authors: England Paula , Bearak Jonathan , Budig Michelle J. , Hodges Melissa J.
Published: December 2016

Motherhood reduces women’s wages. But does the size of this penalty differ between more and less advantaged women? To answer this, we use unconditional quantile regression models with person-fixed effects, and panel data from the 1979 to 2010 National Longitudinal Survey of Youth (NLSY79). We find that among white women, the most privileged—women with high skills and high wages—experience the highest total penalties, estimated to include effects mediated through lost experience. Although highly skilled, highly paid women have fairly continuous experience, their high returns to experience make even the small amounts of time some of them take out of employment for childrearing costly. By contrast, penalties net of experience, which may represent employer discrimination or effects of motherhood on job performance, are not distinctive for highly skilled women with high wages.
Fault detection and isolation in nonlinear systems with partial Reduced Kernel Principal Component Analysis method
Authors: Jaffel Ines , Taouali Okba , Harkat Mohamed Faouzi , Messaoud Hassani
Published: December 2016

In this article, we suggest an extension of our proposed method in fault detection called Reduced Kernel Principal Component Analysis (RKPCA) (Taouali et al., 2015) to fault isolation. To this end, a set of structured residues is generated by using a partial RKPCA model. Furthermore, each partial RKPCA model was performed on a subset of variables to generate structured residues according to a properly designed incidence matrix. The relevance of the proposed algorithm is revealed on Continuous Stirred Tank Reactor.
“A Balance That We Walk”: Characteristics, Attributes, and Behaviors That Promote Healthy American Indian Heterosexual Couple Relationships
Authors: Rink Elizabeth , Ricker Adriann , FourStar Kristofer , Hallum-Montes Rachel
Published: December 2016

The purpose of this study was to investigate the characteristics, attributes, and behaviors that promote healthy American Indian (AI) heterosexual couple relationships. Specific attention was given to the role AI men have in developing and maintaining healthy heterosexual couple relationships. In-depth interviews were conducted with 15 AI participants. Key themes to emerge from analysis of qualitative data included learning about healthy relationships from elders, demonstrating mutual respect and trust, showing respect for women, and honoring a “balance” between love and sex. Findings suggest that interventions for AI men that reinforce Native beliefs, values, and practices are needed to strengthen AI couple relationships.