bluuebunny/crossref_metadata_2025 huggingface dataset:
A dileucine motif in the COOH-terminal domain of NKCC1 targets the cotransporter to the plasma membrane
Authors: Koumangoye Rainelli , Omer Salma , Delpire Eric
Published: March 2019

Na+-K+-2Cl− cotransporter-1 (NKCC1) mediates the electroneutral transport of Na+, K+, and Cl− and is normally localized to the basolateral membrane of polarized epithelial cells. We recently reported the first known solute carrier family 12 member 2 ( SLC12A2) mutation (we call NKCC1-DFX) that causes epithelial dysfunction in an undiagnosed disease program case. The heterozygous mutation leads to truncation of the COOH-terminal tail of the cotransporter, resulting in both mutant and wild-type cotransporters being mistrafficked to the apical membrane of polarized epithelial cells. Here we demonstrate by using consecutive truncations and site-directed mutagenesis of the COOH-terminal domain of NKCC1 that truncation of NKCC1 COOH domain uncouples the cotransporter from the lateral membrane. We identify a dileucine motif that, when mutated, leads to cotransporter accumulation in the cytoplasm and mistrafficking to the apical/subapical region of epithelial cells, thereby recapitulating the phenotype observed with the patient mutation. We show that truncation deletion and LL substitution mutants are trafficked out of the endoplasmic reticulum and trans-Golgi network but accumulate in early and late endosomes where they are degraded.
Changes in the fraction of strongly attached cross bridges in mouse atrophic and hypertrophic muscles as revealed by continuous wave electron paramagnetic resonance
Authors: Galazzo Laura , Nogara Leonardo , LoVerso Francesca , Polimeno Antonino , Blaauw Bert , Sandri Marco , Reggiani Carlo , Carbonera Donatella
Published: March 2019

Electron paramagnetic resonance (EPR), coupled with site-directed spin labeling, has been proven to be a particularly suitable technique to extract information on the fraction of myosin heads strongly bound to actin upon muscle contraction. The approach can be used to investigate possible structural changes occurring in myosin of fiber s altered by diseases and aging. In this work, we labeled myosin at position Cys707, located in the SH1-SH2 helix in the myosin head cleft, with iodoacetamide spin label, a spin label that is sensitive to the reorientational motion of this protein during the ATPase cycle and characterized the biochemical states of the labeled myosin head by means of continuous wave EPR. After checking the sensitivity and the power of the technique on different muscles and species, we investigated whether changes in the fraction of strongly bound myosin heads might explain the contractile alterations observed in atrophic and hypertrophic murine muscles. In both conditions, the difference in contractile force could not be justified simply by the difference in muscle mass. Our results showed that in atrophic muscles the decrease in force generation was attributable to a lower fraction of strongly bound cross bridges during maximal activation. In contrast in hypertrophic muscles, the increase in force generation was likely due to several factors, as pointed out by the comparison of the EPR experiments with the tension measurements on single skinned fibers.
Acute increases in O-GlcNAc indirectly impair mitochondrial bioenergetics through dysregulation of LonP1-mediated mitochondrial protein complex turnover
Authors: Wright JaLessa N. , Benavides Gloria A. , Johnson Michelle S. , Wani Willayat , Ouyang Xiaosen , Zou Luyun , Collins Helen E. , Zhang Jianhua , Darley-Usmar Victor , Chatham John C.
Published: March 2019

The attachment of O-linked β- N-acetylglucosamine ( O-GlcNAc) to the serine and threonine residues of proteins in distinct cellular compartments is increasingly recognized as an important mechanism regulating cellular function. Importantly, the O-GlcNAc modification of mitochondrial proteins has been identified as a potential mechanism to modulate metabolism under stress with both potentially beneficial and detrimental effects. This suggests that temporal and dose-dependent changes in O-GlcNAcylation may have different effects on mitochondrial function. In the current study, we found that acutely augmenting O-GlcNAc levels by inhibiting O-GlcNAcase with Thiamet-G for up to 6 h resulted in a time-dependent decrease in cellular bioenergetics and decreased mitochondrial complex I, II, and IV activities. Under these conditions, mitochondrial number was unchanged, whereas an increase in the protein levels of the subunits of several electron transport complex proteins was observed. However, the observed bioenergetic changes appeared not to be due to direct increased O-GlcNAc modification of complex subunit proteins. Increases in O-GlcNAc were also associated with an accumulation of mitochondrial ubiquitinated proteins; phosphatase and tensin homolog induced kinase 1 (PINK1) and p62 protein levels were also significantly increased. Interestingly, the increase in O-GlcNAc levels was associated with a decrease in the protein levels of the mitochondrial Lon protease homolog 1 (LonP1), which is known to target complex IV subunits and PINK1, in addition to other mitochondrial proteins. These data suggest that impaired bioenergetics associated with short-term increases in O-GlcNAc levels could be due to impaired, LonP1-dependent, mitochondrial complex protein turnover.
Vitamin D receptor activation protects against lipopolysaccharide-induced acute kidney injury through suppression of tubular cell apoptosis
Authors: Du Jie , Jiang Siqing , Hu Zhaoxin , Tang Shiqi , Sun Yue , He Jinrong , Li Zhi , Yi Bin , Wang Jianwen , Zhang Hao , Li Yan Chun
Published: March 2019

Acute kidney injury (AKI) is a common complication of sepsis characterized by a rapid degradation of renal function. The effect of vitamin D on AKI remains poorly understood. Here, we showed that vitamin D receptor (VDR) activation protects against lipopolysaccharide (LPS)-induced AKI by blocking renal tubular epithelial cell apoptosis. Mice lacking VDR developed more severe AKI than wild-type (WT) control mice after LPS treatment, which was manifested by marked increases in body weight loss and accumulation of serum blood urea nitrogen and creatinine as well as the magnitude of apoptosis of tubular epithelial cells. In the renal cortex, LPS treatment led to more dramatic downregulation of Bcl-2, more robust induction of p53-upregulated modulator of apoptosis (PUMA) and miR-155, and more severe caspase-3 activation in VDR knockout mice compared with WT control mice. Conversely, paricalcitol pretreatment markedly prevented LPS-induced AKI. Paricalcitol ameliorated body weight loss, attenuated serum blood urea nitrogen and creatinine accumulation, blocked tubular cell apoptosis, prevented the suppression of Bcl-2, and reversed PUMA and miR-155 induction and caspase-3 activation in LPS-treated WT mice. In HK2 cells, LPS induced PUMA and miR-155 by activating NF-κB, whereas 1,25(OH)2D3blocked PUMA and miR-155 induction by repressing NF-κB activation. Both PUMA and miR-155 target Bcl-2 to promote apoptosis; namely, PUMA inhibits Bcl-2 activity, whereas miR-155 promotes Bcl-2 mRNA degradation and inhibits Bcl-2 protein translation. Collectively, these data provide strong evidence that LPS induces tubular cell apoptosis via upregulating PUMA and miR-155, whereas vitamin D/VDR signaling protects against AKI by blocking NF-κB-mediated PUMA and miR-155 upregulation.
Urine podoplanin heralds the onset of ischemia-reperfusion injury of the kidney
Authors: Kasinath Vivek , Yilmam Osman Arif , Uehara Mayuko , Yonar Merve , Jiang Liwei , Li Xiaofei , Qiu Weiliang , Eskandari Siawosh , Ichimura Takaharu , Abdi Reza
Published: March 2019

Ischemia-reperfusion injury represents one of the most common causes of acute kidney injury, a serious and often deadly condition that affects up to 20% of all hospitalized patients in the United States. However, the current standard assay used universally for the diagnosis of acute kidney injury, serum creatinine, does not detect renal damage early in its course. Serendipitously, we found that the immunofluorescent signal of the constitutive podocyte marker podoplanin fades in the glomerulus and intensifies in the tubulointerstitial compartment of the kidney shortly after ischemia-reperfusion injury in 8- to 10-wk-old male C57Bl/6j mice. Therefore, we sought to define the appearance and course of the podoplanin-positive signal in the kidney after ischemia-reperfusion injury. The tubulointerstitial podoplanin-positive signal increased as early as 2 h but persisted for 7 days after ischemia-reperfusion injury. In addition, the strength of this tubulointerstitial signal was directly proportional to the severity of ischemia, and its location shifted from the tubules to interstitial cells over time. Finally, we detected podoplanin in the urine of mice after ischemia, and we observed that an increase in the urine podoplanin-to-creatinine ratio correlated strongly with the onset of renal ischemia-reperfusion injury. Our findings indicate that the measurement of urine podoplanin harbors promising potential for use as a novel biomarker for the early detection of ischemia-reperfusion injury of the kidney.
Disentangling expectation from selective attention during perceptual decision making
Authors: Simon Alexander J. , Schachtner Jessica N. , Gallen Courtney L.
Published: March 2019

A large body of work has investigated the effects of attention and expectation on early sensory processing to support decision making. In a recent paper published in The Journal of Neuroscience, Rungratsameetaweemana et al. (Rungratsameetaweemana N, Itthipuripat S, Salazar A, Serences JT. J Neurosci 38: 5632–5648, 2018) found that expectations driven by implicitly learned task regularities do not modulate neural markers of early visual processing. Here, we discuss these findings and propose several lines of follow-up analyses and experiments that could expand on these findings in the broader perceptual decision making literature.
Credit Scoring: A Review on Support Vector Machines and Metaheuristic Approaches
Authors: Goh R. Y. , Lee L. S.
Published: March 2019

Development of credit scoring models is important for financial institutions to identify defaulters and nondefaulters when making credit granting decisions. In recent years, artificial intelligence (AI) techniques have shown successful performance in credit scoring. Support Vector Machines and metaheuristic approaches have constantly received attention from researchers in establishing new credit models. In this paper, two AI techniques are reviewed with detailed discussions on credit scoring models built from both methods since 1997 to 2018. The main discussions are based on two main aspects which are model type with issues addressed and assessment procedures. Then, together with the compilation of past experiments results on common datasets, hybrid modelling is the state-of-the-art approach for both methods. Some possible research gaps for future research are identified.
Milk Fat Globule-Epidermal Growth Factor-Factor 8 Reverses Lipopolysaccharide-Induced Microglial Oxidative Stress
Authors: Li Jie , Xu Xiaotian , Cai Xiaoying , Weng Yinlun , Wang Yiping , Shen Qingyu , Shi Xiaolei
Published: March 2019

Oxidative stress plays an important role in various neurological disorders. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) is a regulatory protein for microglia. However, its involvement in microglial oxidative stress has not been established. In this study, we observed microglial oxidative stress in response to lipopolysaccharide (LPS) both in vitro and in vivo. LPS induced significant elevation of TNF-α, IL-6, MDA, and ROS and reduction of GSH and SOD in the mouse brains and primary microglia, which were reversed by MFG-E8 pretreatment. MFG-E8 induced the expression of Nrf-2 and HO-1 that was reduced by LPS incubation. Moreover, LPS-increased Keap-1 expression was reversed by MFG-E8. But the above tendencies were not seen when MFG-E8 was applied alone. The current study established the involvement of MFG-E8 in antioxidant effects during neuroinflammation. It may achieve the effects through the regulation of Keap-1/Nrf-2/HO-1 pathways.
Inhibition of Cytochrome P450 Activities by Sophora flavescens Extract and Its Prenylated Flavonoids in Human Liver Microsomes
Authors: Yim Daeun , Kim Min Jung , Shin Yumi , Lee Su-Jun , Shin Jae Gook , Kim Dong Hyun
Published: March 2019

Sophora flavescens possesses several pharmacological properties and has been widely used for the treatment of diarrhea, inflammation, abscess, dysentery, and fever in East Asian countries. S. flavescens is a major source of prenylated flavonoids, such as sophoraflavone and kushenol. In this study, we examined the effects of S. flavescens extract and its prenylated flavonoids on cytochrome P450 (CYP) isoform activity in human liver microsomes. The extract inhibited CYP2C8, CYP2C9, CYP2C19, and CYP3A activities, with IC50 values of 1.42, 13.6, 19.1, and 50 µg/mL, respectively. CYP2B6 was only inhibited in human liver microsomes preincubated with the extract. CYP3A4 was more strongly inhibited by the extract in the presence of NADPH, suggesting that the extract may inhibit CYP2B6 and CYP3A4 via mechanism-based inactivation. Prenylated flavonoids also inhibited CYP isoforms with different selectivity and modes of action. Kushenol I, leachianone A, and sophoraflavone G inhibited CYP2B6, whereas kushenol C, kushenol I, kushenol M, leachianone A, and sophoraflavone G inhibited CYP3A4 via mechanism-based inhibition. Our results suggest that S. flavescens may contribute to herb–drug interactions when coadministered with drugs metabolized by CYP2B6, CYP2C8, CYP2C9, and CYP3A4.
Surface to Groundwater Interactions beneath the City of Berlin: Results from 3D Models
Authors: Frick Maximilian , Scheck-Wenderoth Magdalena , Schneider Michael , Cacace Mauro
Published: March 2019

Knowing the thermal and hydraulic conditions below major urban centers is of increasing importance in the context of energy and water supply. With this study, focusing on the major urban center of Berlin, Germany, we aim to gain insights on the coupling of surface water bodies to the subsurface thermal and hydraulic field investigating shallow water to deep groundwater interactions. Therefore, we use a 3D structural model of the subsurface, constrained by all available data and observations, as a base for simulations of the coupled transport of fluid and heat. This model resolves the 3D configuration of the main geological units and thus enables us to account for related heterogeneities in physical properties. Additionally, we resolve surface water body geometries with newly available data. To assess how surface water bodies interact with the deeper groundwater at different depths in the model domain, the influence of different hydraulic boundary conditions is quantified, which indicates that the coupling of surface water bodies and groundwater strongly modifies predicted groundwater circulation. Consequently, changes in subsurface temperatures are also predicted, where lakes may account for temperature differences up to ±5°C and rivers could account for up to ±1°C visible at depths ≤-500 m.a.s.l. These differences are mainly connected to changes in the advective component of heat transport caused by the modifications of the hydraulic boundary condition. Pressure-driven heat transport is most efficient where differences between hydraulic heads of aquifers and surface water bodies are highest. This study therefore illustrates the impact of surface to subsurface water interactions in an urban context.
Novel Antibacterial Resin-Based Filling Material Containing Nanoparticles for the Potential One-Step Treatment of Caries
Authors: Angel Villegas Natalia , Silvero Compagnucci M. Jazmin , Sainz Ajá Martin , Rocca Diamela María , Becerra María Cecilia , Fabián Molina Gustavo , Palma Santiago Daniel
Published: March 2019

The aim of this work was to study the application of resin filling containing nanomaterials for the potential treatment of caries. Zinc nanoparticles (ZnO@NP, 50 nm) were chosen for their antimicrobial capacity against aerobic bacteria, and here, they have proved to be bactericidal against anaerobic bacterial strains (Streptococcus mutans, Streptococcus mitis, and Lactobacillus spp.). Potential mechanism of action is proposed based on microbiological assays and seems to be independent of oxidative stress because the nanoparticles are effective in microaerophilic conditions. The loading of nanoparticles on the demineralized dental surface and their infiltration power were significantly improved when ZnO@NP were carried by the resin. Overall, this material seems to have a high potential to become a one-step treatment for caries lesions.
Phase Noise Cancelation Based on Polarization Modulation for Massive MIMO-OFDM Systems
Authors: Nie Yao , Feng Chunyan , Wu Huan , Liu Fangfang , Guo Caili , Fu Maosheng
Published: March 2019

In massive multiple-input multiple-output (MIMO) systems, phase noise introduced by oscillators can cause severe performance loss. It leads to common phase error and intercarrier interference in massive MIMO-OFDM uplink. To solve the issue, a novel phase noise cancelation scheme based on polarization modulation for the massive MIMO-OFDM system is proposed. We first introduce the polarization modulation (PM) exploited in massive MIMO-OFDM uplink. Then, by exploiting the zero-forcing detection, we analyze the asymptotically ICI and the distribution of the transformed noise under different XPD values. Furthermore, we demonstrate that phase noise can be asymptotically canceled and only the transformed additive white Gaussian noise exists as the number of antennas at the base station is very large. Moreover, we derive the instantaneous signal-to-noise ratio (SNR) on each subcarrier and analyze the ergodic capacity. To increase the ergodic capacity performance further, a joint modulation scheme combining the PM and 2PSK is proposed and the ergodic capacity performance of the joint modulation is discussed. The simulation results show that the proposed scheme can effectively mitigate phase noise and achieve a higher ergodic capacity.
A New Efficient Modified First‐Order Shear Model for Static Bending and Vibration Behaviors of Two‐Layer Composite Plate
Authors: Nam Vu H. , Nam Nguyen H. , Vinh Pham V. , Khoa Dang N. , Thom Do V. , Minh Phung V.
Published: March 2019

A two‐layer (connected by stubs) partial composite plate is a structure with outstanding advantages which can be widely applied in many fields of engineering such as construction, transportation, and mechanical. However, studies are scarce in the past to investigate this type of structure. This paper is based on the new modified first‐order shear deformation plate theory and finite element method to develop a new four‐node plate element with nine degrees of freedom per node for static bending and vibration analysis of the two‐layer composite plate. The numerical results are compared to published data for some special cases. The effects of some parameters such as the boundary condition, stiffness of the connector stub, height‐to‐width ratio, thickness‐to‐thickness ratio between two layers, and aspect ratio are also performed to investigate new numerical results of static bending and free vibration responses of this structure.
The Grey Theory Combining the Taguchi Method for the Best Parameters: A Case Study of Polishing M300 Steel
Authors: Wu Xiaojun , Yang Yang , Tong Xin , Shu Xiao , Li Yan
Published: March 2019

M300 steel, as high‐chromium alloy steel with strong wear resistance and corrosion resistance, is widely used in the manufacture of complex profile molds and aerospace military equipment such as missile parts. However, there are still some problems such as the contradiction between productivity and surface quality in the polishing process for M300 steel. Therefore, in order to solve these problems, surface polishing experiments on M300 steel, single‐factor and orthogonal experiments, and parameters’ optimization were studied. In this paper, orthogonal experiments are conducted for four selected machining parameters: grain size (A), grinding speed (B), cutting depth (C), and feed rate (D) on a grinding machine. The experiment and parameters’ optimization of the ball type abrasive tool polishing M300 were investigated by a five‐axis machining center, electronic analytical balance, and three‐dimensional surface topographer, and the optimal process parameters and preferred intervals were optimized. The optimal parametric condition obtained for simultaneous minimization of surface roughness (Ra) and maximization of material removal rate (MRR) is as follows: grain size=#320, grinding speed=4500 r/min, cutting depth=0.4 mm, and feed rate=80 mm/s. The above parametric combination has been validated by confirmatory tests.
Aerothermoelastic Analysis of a Hypersonic Vehicle Based on Thermal Modal Reconstruction
Authors: Chen Zhiqiang , Zhao Yonghui
Published: March 2019

Hypersonic vehicles operate in a severe aerodynamic heating environment, which has a significant impact on their structural dynamic characteristics. Therefore, aerodynamic heating effects cannot be ignored when performing an aeroelastic analysis for a hypersonic vehicle. However, incorporating aerodynamic heating effects into the fluid-structural coupling analysis will result in extreme computational costs. Actually, after experiencing a sustained flight in a fixed state, the vehicle will eventually reach the thermodynamic equilibrium. Thus, the aeroelastic analysis can be efficiently performed by using the structural dynamic characteristics of the heated vehicle operating in each equilibrium state. The effects of aerodynamic heating show that the modal frequencies and modal shapes of the flexible structure are bound to change significantly in comparison with the unheated structure. In this paper, a method of thermal modal reconstruction is developed in order to directly generate the structural mode shapes and frequencies within the given parameter space without having to solve a high-fidelity thermal and structural problem. Once the modal data are available, the multivariate interpolation in a tangent space to Grassmann manifold is used to generate the modal matrix at the arbitrary selected parameter point. Besides, the Kriging interpolation method is used to establish the approximate relationships between natural frequencies and sampling points. Finally, an example of an aerodynamic heated control surface structure is used to validate the effectiveness of the proposed aerothermoelastic framework. It is demonstrated that the developed thermal modal reconstruction method has good robustness, very high computational efficiency, and sufficient accuracy over a wide parametric domain.
Effects of Exercise Combined with Finasteride on Hormone and Ovarian Function in Polycystic Ovary Syndrome Rats
Authors: Wu Chuyan , Jiang Feng , Wei Ke , Lin Feng , Jiang Zhongli
Published: March 2019

Exercise can reduce androgen and insulin levels in polycystic ovary syndrome (PCOS) patients. Finasteride is also presumed to improve the developing follicle environment. Therefore, the aim of this study was to observe the effects of the combination of exercise and finasteride therapy on hormone levels and ovarian morphology in rats with polycystic ovary syndrome. Forty female rats were randomly divided into five groups (n=8 each group): the PCOS sedentary group (P-Sed), PCOS exercise group (P-Ex), PCOS finasteride and sedentary group (P-FSed), and PCOS finasteride and exercise group (P-FEx), and healthy, age-matched rats were used as controls (CO). The results indicated that the levels of FINS in the P-FEx group were significantly lower than those in the P-Sed and P-FSed groups, while the ratio of fasting blood glucose (FBG)/fasting serum levels of insulin (FINS) in the P-FEx group was significantly higher than that in the P-Sed and P-FSed groups. Compared to the P-FEx group, serum levels of TT (total testosterone) in the P-Sed and P-FSed groups were significantly increased. The thickness of the follicular membrane and the number of atresia follicles in the P-FEx and CO groups were significantly lower than those in the P-Sed group, but there was no significant difference between the P-Ex and P-Sed groups. These results show that the combined usage of exercise and finasteride does not alter the effects of exercise on increasing insulin sensitivity and reducing androgen levels. There is also a synergistic effect of exercise and finasteride on the morphology of the ovary, including a reduced number of atresia follicles and thickness of the follicular membrane.
Chinese Herbal Complex ‘Bu Shen Jie Du Fang’ (BSJDF) Modulated Autophagy in an MPP+-Induced Cell Model of Parkinson’s Disease
Authors: Liu Cuifang , Huang Xiaobo , Qiu Shengxiang , Chen Wenqiang , Li Weihong , Zhang Haiyan , Wang Tao , Wang Xue , Wu Xiling
Published: March 2019

Autophagy plays an important role in the development of Parkinson disease (PD). Previous studies showed that autophagy could protect cells from α-synuclein toxicity and promote functional coupling of mitochondria. But it is still a question whether modulating autophagy can be used to treat PD. In traditional Chinese medicine, a specific Chinese herbal complex called Bu Shen Jie Du Fang (BSJDF) has a long history of treating motor impairments similar to Parkinson disease, while its mechanism is still unclear. As a pilot study, we aimed to evaluate the efficacy and its mechanism of Bu Shen Jie Du Fang in an MPP+-induced cell model of Parkinson’s disease. And the phase contrast microscope (PCM) revealed that the BSJDF group had the greatest surviving cell counts compared with all other treated cell groups except the normal group. And Cell Counting Kit 8 (CCK8) assays showed a similar result. In BSJDF group, 3.7 ×107 cells/dish was identified by hemocytometer counts, which was significantly higher than other groups except the normal cells (p<0.05). In the BSJDF group, autophagy can be observed by transmission electron microscopy (TEM). Protein expression of Atg12 and LC3 in the BSJDF group was upregulated compared to the PD model group (p<0.05). Atg12 mRNA expression was also upregulated in the BSJDF group (p<0.05). In conclusion, our study indicated that the therapeutic mechanisms of BSJDF may be mediated by stimulating autophagy, and modulating autophagy can be used to treat PD.
Intratumoral Sterol-27-Hydroxylase (CYP27A1) Expression in Relation to Cholesterol Synthesis and Vitamin D Signaling and Its Association with Lethal Prostate Cancer
Authors: Khan Nabeela A. , Stopsack Konrad H. , Allott Emma H. , Gerke Travis , Giovannucci Edward L. , Mucci Lorelei A. , Kantoff Philip W.
Published: March 2019

Background:

Higher intratumoral cholesterol synthesis is associated with a worse prognosis in prostate cancer. The vitamin D–regulated enzyme sterol-27-hydroxylase (CYP27A1) converts cholesterol to 27-hydroxycholesterol, potentially lowering intracellular cholesterol levels. We hypothesized that low CYP27A1 expression is associated with high cholesterol synthesis, low vitamin D signaling, and higher risk of lethal prostate cancer.

Methods:

In 404 patients from the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (HPFS) and the Physicians’ Health Study (PHS), we assessed intratumoral CYP27A1 expression and proxies of cholesterol synthesis using transcriptome profiling, prediagnostic plasma 25-hydroxyvitamin D [25(OH)D; n = 132], and intratumoral vitamin D receptor protein expression (VDR; n = 300). Patients were followed for metastases and prostate cancer mortality (lethal cancer; median follow-up, 15.3 years).

Results:

CYP27A1 expression was lower in tumors with higher Gleason grade and higher expression of cholesterol synthesis enzymes, including the second rate-limiting enzyme, SQLE. We did not detect consistent associations between CYP27A1 and 25(OH)D, VDR, or CYP24A1 mRNA expression. Lower CYP27A1 was associated with higher risk of lethal cancer in both cohorts, independent of SQLE [adjusted OR for lowest vs. highest quartile of CYP27A1, 2.64; 95% confidence interval (CI), 1.24–5.62]. This association was attenuated when additionally adjusting for Gleason grade (OR, 1.76; 95% CI, 0.75–4.17).

Conclusions:

Low CYP27A1 expression was associated with higher cholesterol synthesis and a higher risk of lethal disease.

Impact:

These observations further support the hypothesis that intratumoral cholesterol accumulation through higher synthesis and decreased catabolism is a feature of lethal prostate cancer.
Lack of Association between Human Papillomavirus Types 6 and 11 Genetic Variants and Cervical Abnormalities: The Ludwig–McGill Cohort Study
Authors: Sichero Laura , El-Zein Mariam , Ferreira Silvaneide , Franco Eduardo L. , Villa Luisa L.
Published: March 2019

Background:

Human papillomavirus (HPV) types 6 and 11 are mainly associated with the development of genital warts and recurrent respiratory papillomatosis. We examined intratypic genetic variability of both viral types with the development of cervical cytologic abnormalities in Brazilian women.

Methods:

We used PCR sequencing to characterize variants of HPVs 6 and/or 11 in cervical swabs from women in the Ludwig–McGill Cohort Study. We used a binomial generalized estimating equations (GEE) model with logit link to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations between HPV 6 and 11 variants and cytologic abnormalities.

Results:

B1 and B3 HPV6 and A2 HPV11 variants were the most common isolates identified. Compared with HPV6-negative women, the ORs among women harboring HPV6 B1 or B3 variants were 6.3 (95% CI, 2.3–17.0) and 2.3 (95% CI, 0.6–9.7) for atypical cells of undetermined significance (ASCUS)/low squamous intraepithelial lesions (LSIL), respectively, and 1.7 (95% CI, 0.6–5.1) and 1.2 (95% CI, 0.3–4.7) for ASCUS/LSIL/high squamous intraepithelial lesions (HSIL). Respective ORs were 5.0 (95% CI, 1.7–14.6) and 2.8 (95% CI, 1.0–8.1) upon comparing women with HPV11 A2 variants to HPV11-negative women. All associations disappeared when adjusting for coinfections with high-risk HPV types.

Conclusions:

Our data do not support an association between low-risk HPVs 6 and 11 genetic variability and cervical abnormalities.

Impact:

Risk of cervical cytologic abnormalities is not affected by intratypic polymorphism in HPVs 6 and 11.
New and Emerging Tobacco Products and the Nicotine Endgame: The Role of Robust Regulation and Comprehensive Tobacco Control and Prevention: A Presidential Advisory From the American Heart Association
Authors: Bhatnagar Aruni , Whitsel Laurie P. , Blaha Michael J. , Huffman Mark D. , Krishan-Sarin Suchitra , Maa John , Rigotti Nancy , Robertson Rose Marie , Warner John J. ,   On behalf of the American Heart Association
Published: March 2019

The advent of new tobacco products such as electronic cigarettes and the dramatic rise in their use, especially by adolescents and young adults, are significant public health concerns. Electronic cigarettes have become the most popular tobacco products for youth and adolescents in the United States and are attracting youth to new avenues for nicotine addiction. Although these products may have benefit by helping some smokers quit or to move to a less harmful product, the long-term health effects of these products and the net public health effect associated with their use remain unclear and widely debated. There is increasing concern that the use of newer tobacco products may catalyze transition to the use of other tobacco products or recreational drugs, particularly in young adults. Therefore, there is urgent need for robust US Food and Drug Administration regulation of all tobacco products to avoid the significant economic and population health consequences of continued tobacco use. Although the American Heart Association acknowledges that the ultimate endgame would be an end to all tobacco and nicotine addiction in the United States, it supports first minimizing the use of all combustible tobacco products while ensuring that other products do not addict the next generation of youth and adolescents. The endgame strategy needs to be coordinated with the long-standing, evidence-based tobacco control strategies that have significantly reduced tobacco use and initiation in the United States.
Description of Ektaphelenchus cupressi n. sp. (Nematoda: Ektaphelenchinae) from Iran
Authors: Golhasan Behrouz , Abdollahpour Mehdi , Fang Yiwu , Abolafia Joaquín , Heydari Ramin
Published: March 2019

Ektaphelenchus cupressi n. sp. was isolated during a survey of nematodes associated with bark samples of a dead cypress tree (Cupressus sempervirens) in Mazandaran province, northern Iran. The new species is characterised by a female body length of 612 (520-693) μm, stylet 17-19 μm long with wide lumen and lacking basal swellings, head region hemispherical in lateral view and slightly offset from the body contour by a shallow constriction, three incisures in the lateral field, excretory pore situated anterior to level of metacorpus valve, hemizonid not seen, post-uterine sac 29-35 μm long, shape of the tail terminus, and arrangement of the male caudal papillae. By a combination of morphological characters, e.g., stylet without knobs or swellings at the base, short conical tail, PUS length, and only a vestigial anus and rectum in most individuals, the new species shares similarities with species belonging to three genera, i.e., Anomyctus, Ektaphelenchus, and Seinura. Phylogenetic analysis based on small subunit (SSU) and partial large subunit (LSU) sequences of rDNA confirmed its status as a new species.
On the Ground of Images: Sacred Dogs and Monstrous Truth
Authors: Warnek Peter
Published: March 2019

The article takes up the question of the “truth” of images by means of a somewhat playful reflection upon our human kinship with canine life and by considering the (perhaps surprisingly) recurrent images of dogs of all shapes and sizes within the philosophical tradition. Here there is occasion to consider both Socrates and Confucius, who had a special fondness for dogs and who were at times compared to dogs themselves. The paper begins with a reading of Kant’s schematism in the First Critique, as an operation that would establish a mediating relation between the concepts of the understanding and sensible intuitions, and ends with a meditation upon the dog-themed painting, “Dark Room,” by the contemporary artist, Alan Loehle. Kant accounts for our ability to grasp that we see a dog (his example!) by introducing a mysterious distortional skewing or Verzeichnung, which as a power of the imagination is able to freely sketch what appears for it within the sensible. The sense of this Kantian skewing or sketching thereby anticipates what Heidegger names the essential Verunstaltung belonging originally to the event of truth. The last half of the paper turns to Jean-Luc Nancy’s difficult but provocative work on the abysmal ground of images and attempts to show in this way how our human kinship with canine life exposes us to what Nancy would think, following Heidegger, as the elemental strife between earth and sky.
Age structure and body size of a critically endangered species, Acanthodactylus harranensis (Squamata: Lacertidae) and its demography
Authors: Beşer Nurettin , Ilgaz Çetin , Kumlutaş Yusuf , Avcı Aziz , Candan Kamil , Üzüm Nazan
Published: March 2019

Within reptiles, lizards cover less area across the globe than snakes do. One out of every seven known species of lizards in the world is found only in its type locality. Acanthodactylus harranensis Baran, Kumlutaş, Lanza, Sindaco, Ilgaz, Avcı & Crucitti, 2005, is one of these species. It is an endemic lizard species in Turkey with a very small area of occupancy and is listed in the critically endangered category (CR) by the IUCN. Here we document the age structure and body size of A. harranensis using skeletochronological methods for the first time and aim to point out current problems and contribute to an understanding of its demography. The mean age of males was found to be significantly higher than that of females. The maximum life span was 10 years in males while it was 9 years in females. The 8-year-old age group contained a higher number of individuals than any other age group. The mean snout-vent length of specimens was not significantly different between the sexes. As in many other lizards, A. harranensis exhibits a low-level male-biased sexual dimorphism. Acanthodactylus harranensis also displayed a considerably bigger body size than other studied lacertids from Şanlıurfa province. The data presented in this study may contribute to future conservation efforts for this endangered species.
Joint Criminal Enterprise on the Decline: A Step Further in the ‘Self-Becoming’ of International Criminal Law?
Authors: Caeiro Pedro , Costa Joana
Published: March 2019

This article uses the legal construct ‘joint criminal enterprise’ (jce) as a focal point of the tensions between international criminal law (icl) and common criminal law. Drawing on the assumption that an over-arching concept of the criminal law in genere is plausible, and that icl is a special branch stemming therefrom, the authors start by characterising jce and by assessing the possible incompatibility of some of its forms with the principles of legality, voluntary act and guilt. The authors then question whether jce could be validated under a different understanding of icl (as an autonomous legal branch, or, at least, as a special branch within criminal law abiding by different principles). Finally, it is argued that the apparent decline of jce might be another instance where icl becomes itself ‘more wholly’.
Irregular Migration by Sea: Interception and Rescue Interventions in Light of International Law and the EU Sea Borders Regulation
Authors: Koka Enkelejda , Veshi Denard
Published: March 2019

Since 2011, due to the Syrian civil war, Libya’s institutional breakdown and Eritrea’s political unrest, record high numbers of irregular migrants have been arriving at the EU’s south-eastern external borders, publicly known as the ‘Europe’s refugee crisis’. The most pressurised borders have been those of Greece and Italy. The human smuggler’s ‘organised refugee’ strategy has identified various legal issues resulting from the application of parallel legal frameworks both at regional and at international level. The EU Member States’ policy-making response to human smuggling has created loopholes through conflicting interpretations of the international legal framework on search and rescue and the inconsistent application of human rights law. Hence, this article will argue that although the International Convention on Maritime Search and Rescue (SAR) and the EU Sea Borders Regulation purportedly adopted to set out clear rules on when to initiate search and rescue, have not addressed the issue of responsibility for and the consequences of failed rescue scenarios by inactive SAR States; thereby creating a gap in the legal framework on State responsibility for negligent or intentional failed rescues.
Russian Organised Crime in Spain: Its Criminal Law Treatment and some Criminological Considerations Regarding its Characteristics and Prevalence
Authors: Kazyrytski Leanid , Sukharenko Alexander
Published: March 2019

The present article describes organised criminality in Spain from a criminal law and criminological perspective. Special emphasis is placed on the problem of organised Russian criminality and its increasing media impact is highlighted. A description of Russian organised crime is provided, which considers some of the organisational characteristics and the criminal activity conducted. In addition, analysis of police data evaluates its impact on the overall context of organised crime groups which operate in this country. It is emphasized that despite the notorious presence of Russian criminal organisations, these do not constitute the main actors in the criminal landscape.
Between Erasmus and More, Abraxa(s), an Anamorphic Name
Authors: Perona Blandine
Published: March 2019

Before Utopus conquered the island, it was called Abraxa. To create its initial name, Thomas More shortened the name of a deity, invented by the Syrian Christian gnostic teacher Basilides, Abraxas. This note seeks to explain this change by studying the occurrences of the word Abraxas in Erasmus’ work (edition of St Jerome’s works, Praise of Folly). Abraxa then appears as an anamorphic name, an effort of wisdom and a sign of pride. The utopian wisdom is condemned to death. The dialogue between Erasmus and More through this word shows how much the anamorphic woodcuts of Ambrosius Holbein are an excellent illustration of what Abraxa/Utopia is: an ironic invention of a self-conscious pride.
The Democratic Constitution: Butler and Posner on Pragmatism, Democracy, and Adjudication
Authors: Vannatta Seth
Published: March 2019

In this review essay, I offer a summary of Brian E. Butler’s The Democratic Constitution: Experimentalism and Interpretation. Butler’s democratic experimentalism offers the thesis that democracy needs to be protected democratically rather than by relying on the judicial supremacy over constitutional interpretation by the Supreme Court. Butler illustrates what democratic experimentalism looks like through a close reading of key cases showing the virtues of an on-going, open-ended, empirical, fallibilist, and collaborative approach to constitutional interpretation against rival formalist and exclusionary theories. Butler relies on Richard Posner’s iconoclastic empirical approach to adjudication in advancing his thesis. However, Posner is skeptical of the Deweyan democracy Butler deploys to illustrate the democratic constitution.

Further, Posner dismisses the philosophical pragmatism of Peirce and Dewey that Butler uses to ground his theory. Because of Butler’s reliance on Posner’s judicial practice and his side-stepping of Posner’s views on democracy and philosophical pragmatism, I ask how Butler’s proposal stands in relation to the ways it departs from Posner’s theory, if not his practice.
Analytic Philosophy and the Need for Pragmatist Metaphysics
Authors: Hedrick Lisa Landoe
Published: March 2019

This article addresses the problem of intentionality in Analytic philosophy. It begins with an assessment of post-Sellarsian scholarship, with primary attention to the work of Richard Rorty, Donald Davidson, Robert Brandom, and John McDowell. I argue that contemporary Analytic discourse on intentionality not only needs, but internally warrants, a pragmatist metaphysics in order to adequately and accurately communicate its public relevance—particularly in ethics. I suggest the metaphysics of Alfred North Whitehead as consonant with the sort of metaphysics needed in order to correct tacit presuppositions currently limiting Analytic treatments of intentionality and, in turn, the possibility of ethical critique without ethnocentrism. The resultant proposal is for a “modest” metaphysics, not unlike that for which Jeffrey Stout has called.
Pragmatism without Progress: Affect and Temporality in William James’s Philosophy of Hope
Authors: Sheehey Bonnie
Published: March 2019

Philosophers and intellectual historians generally recognize pragmatism as a philosophy of progress. For many commentators, pragmatism is tied to a notion of progress through its embrace of meliorism – a forward-looking philosophy that places hope in the future as a site of possibility and improvement. I complicate the progressive image of hope generally attributed to pragmatism by outlining an alternative account of meliorism in the work of William James. By focusing on the affectivity and temporality of James’s meliorism, I argue that James offers a non-progressivist version of hope that is affectively tempered by melancholy and oriented temporally toward the present.
Dewey’s Conceptualization of the Public as Polity Contextualized: The Struggle for Democratic Control over Natural Resources and Technology
Authors: Midtgarden Torjus
Published: March 2019

This article explores John Dewey’s conceptualization of the public as polity in his lecture notes from 1928. Dewey’s conceptualization suggests an account of the democratic legitimacy of public regulation of economic activities by focusing on polity members’ mutual interest. Contextualized through Dewey’s involvement in practical politics the article specifies the conceptualization by a policy focus on natural resources and technology, and explores and discusses it through two issues for democratic control over policy development: centralization of power in federal government; and the failure to understand, predict and control consequences of technology. Finally, exploring its relevance in a context of economic globalization the article rearticulates the conceptualization in terms of transnational relations and solidarities, using the transnational peasant organization La Via Campesina as an example.
Resisting Empathy Bias with Pragmatist Ethics
Authors: Kidder William
Published: March 2019

The paper employs a pragmatist perspective on ethics to address the problem of empathy bias, an empirically documented phenomenon in which one’s ability to empathize with another is diminished simply because of that other’s membership in a perceived out-group. I first argue that the philosophical commitments that I take to be distinctive of pragmatism, specifically fallibilism, anti-absolutism, and democracy, require proactive empathetic engagement as a central component of moral inquiry. While this may initially seem to leave pragmatism vulnerable to concerns about empathy bias, I argue that the pragmatist is uniquely equipped to provide a particular sort of response to the problem: a response that does not jettison empathy from moral judgment, but rather seeks to utilize awareness of bias to appropriately correct empathetic engagement when addressing moral problems.
Sufi Vocabulary, but Avicennan Philosophy
Authors: Rapoport Michael A.
Published: March 2019

In the more than 125 years since A.F. Mehren included Chapters VIII–X of al-Išārāt wa-l-tanbīhāt in his anthology of Ibn Sīnā’s allegedly mystical treatises, scholars have used the presence of Sufi vocabulary in these chapters as evidence of Ibn Sīnā’s mysticism. Yet, his use of Sufi terminology has received little dedicated, critical study. Through careful philological analysis, this study demonstrates that even though Ibn Sīnā appropriated technical vocabulary from Sufism, the meanings that he applied to those terms agree with his philosophical system. His use of these terms is not evidence of experimentation with a mystical, suprarational method of cognition.
The Evolution of W. H. Smith’s Bookselling Strategies and Responsibilities, from the Edwardians to a More Permissive Age
Authors: Macdonald Kate
Published: March 2019

This article describes W. H. Smith’s bookselling strategies in the 20th century, and how the firm handled the question of whether it should supply potentially offensive publications to the public, in the 1960s and early 1970s. Its internal debate centred on avoiding adverse publicity and challenging the firm’s moral values. This research-based discussion draws attention to the relationships between booksellers and the buying public in Britain, and the expectations they each had of the other. The research indicates the wider implications for how we study print culture and book history, and the importance of the modern bookselling archive.
The Academic Book of the Future
Authors: Rayner Samantha
Published: March 2019

This paper explores the contexts in which the academic books of the future in the arts and humanities (A&H) are being shaped, with the aim of demonstrating how crucial it is that the communities of practice that produce those books continue to work together to build better bridges of understanding and collaboration. There is particular reference to the Arts and Humanities Research Council/ British Library Academic Book of the Future Project (2014–2017) and to a case study of Sir Thomas Malory’s Le Morte Darthur.