bluuebunny/crossref_metadata_2025 huggingface dataset:
Female sexual dysfunction in multiple sclerosis: Results of a survey among Dutch urologists and patients
Authors: Scheepe Jeroen R. , Alamyar Mustafa , Pastoor Hester , Hintzen Rogier Q. , Blok Bertil F.M.
Published: October 2015

Aims

The objective of this study was to determine the prevalence of female sexual dysfunction (FSD) in patients with Multiple Sclerosis (MS) in one of the leading MS centers in the Netherlands. Furthermore, we evaluated the practice patterns of members of the Dutch Urological Association (DUA) with respect to FSD.

Methods

A self‐administered Web‐based questionnaire for physicians was mailed to all 467 members of the DUA. The questions covered different topics in female sexuality. For the patient survey the Female Sexual Function Index (FSFI) was used.

Results

The response rate of the physicians survey was 42% (n = 194). Sixty‐one percent of the responders reported to ask their female patients about their sexual function. Thirty‐nine percent of the physicians did not ask their patients about sexuality. The majority indicated that they lacked knowledge on FSD or found discussing sexuality not relevant for their practice.

The response rate of the patient survey was 28% (n = 85). According to the FSFI questionnaire 32% of the sexually active MS patients experienced FSD. Women with FSD scored low on all subdomains of the FSFI questionnaire. In particular, desire, arousal, lubrication, and the ability to achieve orgasm were affected.

Conclusions

The prevalence of FSD in MS patients in our center is about 32%. Overall, many members of the DUA do not screen for sexual dysfunction in female patients because of lack of knowledge on FSD. Better and more structured education of urologists and residents in urology on FSD in The Netherlands is urgently needed. Neurourol. Urodynam. 36:116–120, 2017. © 2015 Wiley Periodicals, Inc.
Strain gradient stabilization with dual stress points for the meshfree nodal integration method in inelastic analyses
Authors: Wu Cheng‐Tang , Chi Sheng‐Wei , Koishi Masataka , Wu Youcai
Published: October 2015

A nonlinear nodal‐integrated meshfree Galerkin formulation based on recently proposed strain gradient stabilization (SGS) method is developed for large deformation analysis of elastoplastic solids. The SGS is derived from a decomposed smoothed displacement field and is introduced to the standard variational formulation through the penalty method for the inelastic analysis. The associated strain gradient matrix is assembled by a B‐bar method for the volumetric locking control in elastoplastic materials. Each meshfree node contains two coinciding integration points for the integration of weak form by the direct nodal integration scheme. As a result, a nonlinear stabilized nodal integration method with dual nodal stress points is formulated, which is free from stabilization control parameters and integration cells for meshfree computation. In the context of extreme large deformation analysis, an adaptive anisotropic Lagrangian kernel approach is introduced to the nonlinear SGS formulation. The resultant Lagrangian formulation is constantly updated over a period of time on the new reference configuration to maintain the well‐defined displacement gradients as well as strain gradients in the Lagrangian computation. Several numerical benchmarks are studied to demonstrate the effectiveness and accuracy of the proposed method in large deformation inelastic analyses. Copyright © 2015 John Wiley & Sons, Ltd.
Allylamine and Allyl Alcohol Plasma Copolymerization: Synthesis of Customizable Biologically‐Reactive Three‐Dimensional Scaffolds
Authors: Hawker Morgan J. , Pegalajar‐Jurado Adoracion , Hicks Kiah I. , Shearer Jeffrey C. , Fisher Ellen R.
Published: October 2015

Plasma copolymerization is a powerful plasma‐enhanced chemical vapor deposition (PECVD)‐based technique, and offers a distinct advantage over single‐precursor PECVD of being able to deposit films with tunable functionality by adjusting the plasma precursor ratio. Here, an allylamine/allyl alcohol plasma copolymerization system was used to modify two‐dimensional (2D) and three‐dimensional (3D) substrates for biomedical applications. Films with customizable and predictable nitrogen and oxygen content, as well as surface wettability, were deposited on both Si wafers and 3D polymer scaffolds across a range of copolymerization conditions. Additionally, the bioreactivity of plasma‐modified materials was evaluated using both human dermal fibroblast and E coli attachment studies.
A pilot study of photoacoustic imaging system for improved real‐time visualization of neurovascular bundle during radical prostatectomy
Authors: Horiguchi Akio , Tsujita Kazuhiro , Irisawa Kaku , Kasamatsu Tadashi , Hirota Kazuhiro , Kawaguchi Makoto , Shinchi Masayuki , Ito Keiichi , Asano Tomohiko , Shinmoto Hiroshi , Tsuda Hitoshi , Ishihara Miya
Published: October 2015

BACKGROUND

Photoacoustic imaging, a noninvasive imaging based on optical excitation and ultrasonic detection, enables one to visualize the distribution of hemoglobin and acquire a map of microvessels without using contrast agents. We examined whether it helps visualize periprostatic microvessels and improves visualization of the neurovascular bundle.

METHODS

We developed a photoacoustic imaging (PAI) system with a hand‐held probe combining optical illumination and a conventional linear array ultrasound probe. In experiments with a phantom model, it was able to visualize vessels with diameters as small as 300 μm within a depth of 10 mm. We also developed a TRUS type probe for our photoacoustic imaging system and used it to intraoperatively monitor periprostatic tissues in seven patients with clinically organ‐confined prostate cancer who were undergoing non‐nerve‐sparing retropubic radical prostatectomy. Images of periprostatic tissues from resected prostatectomy specimens were also obtained using the linear photoacoustic probe, and the consistency of the microvessel distribution and co‐existence of nerve fibers was examined by double immunostaining of paraffin‐embedded sections with anti‐CD31 and anti‐S‐100 antibodies.

RESULTS

Intraoperative monitoring of periprostatic tissues with the TRUS photoacoustic probe showed substantial signals on the posterolateral surface of the prostate and clearly demonstrated the location and extent of the neurovascular bundle better than does TRUS alone. Photoacoustic images of the periprostatic tissues in resected specimens also showed substantial signals that were especially strong on the posterolateral surface of the prostate. Nerve fibers were closely co‐localized with periprostatic microvessels and the pattern of their distribution was consistent with that of PAI signals.

CONCLUSIONS

The intraoperative photoacoustic imaging located the microvascular complex in the neurovascular bundle. Moreover, the neurovascular bundle was easier to identify by PAI than by TRUS alone, suggesting that PAI could be helpful in nerve‐sparing radical prostatectomy. Prostate 76:307–315, 2016. © 2015 Wiley Periodicals, Inc.
Semi‐transparent NiO/ZnO UV photovoltaic cells
Authors: Karsthof R. , Räcke P. , von Wenckstern H. , Grundmann M.
Published: October 2015

Semi‐transparent pn‐heterojunctions were fabricated from pulsed laser deposited (PLD) n‐type ZnO and DC magnetron sputtered p‐type NiO, working as UV‐active solar cells. The complete cell stack has an average transmission of 46% in the visible spectral range and an optical absorption edge at 380 nm. The diodes exhibit high current rectification of up to eight orders of magnitude at 2 V. Upon illumination with a solar simulator, the devices show photovoltaic activity with open‐circuit voltages of up to 520 mV, short‐circuit current densities of 0.5 mAcm, and a maximum external quantum efficiency of 55%. However, we observed rather low fill factors of the current–voltage characteristics of around 40%, resulting in total power conversion efficiencies of around 0.1% and efficiencies in the UV range of 3.1%. To identify possible loss mechanisms, the voltage‐dependent efficiency of carrier collection was calculated. The data were fitted using a model that considers recombination losses at the NiO/ZnO interface as well as within the electric field region, yielding a high hole interface recombination velocity of 1cm s. We conclude that the carrier collection efficiency is strongly deteriorated by recombination losses at the NiO/ZnO interface, causing a strong bending of the jV characteristics under illumination and thereby low fill factors.
Contrasting structures between the decoupled and coupled states of the stable boundary layer
Authors: Acevedo Otávio C. , Mahrt Larry , Puhales Franciano S. , Costa Felipe D. , Medeiros Luiz E. , Degrazia Gervásio A.
Published: October 2015

Different aspects of the stable boundary‐layer structure are contrasted between the very stable and the weakly stable regimes from a new point of view. This study finds a limit wind speed, referred to as the crossover threshold, when the average vertical gradient of the turbulent kinetic energy switches sign at all observational levels. When the wind speed exceeds this transition, the entire stable boundary layer becomes vertically fully coupled. Consequently the very stable boundary layer in this study is considered as a decoupled regime, while the weakly stable state is referred to as a coupled regime. It is shown that the vertical profiles of other quantities, such as friction velocity, heat flux and thermal gradients are strikingly different between the two coupling states.

Decomposition of turbulent kinetic energy and heat flux into temporal scales indicates overlapping of non‐turbulent sub‐mesoscale flow with turbulence in the decoupled case, while there is a clearer scale distinction between the two types of motions when coupling takes place. The turbulent kinetic energy budget is dominated by dissipation and shear production in both coupling states. However, the relative importance of the buoyant destruction term is shown to be appreciably larger in the decoupled regime. In the heat flux budget equation, buoyant destruction is larger in magnitude than production by the thermal gradient in the decoupled case, but not when there is full coupling. These results indicate that the surface heat flux plays a major role in controlling the stable boundary‐layer state, as previously proposed. For the entire dataset, the frequency distributions of turbulence quantities near the surface are shown to be bimodal. The two modes are associated with the two coupling states, each well described by independent log‐normal distributions.
Red Blood Cell Membrane as a Biomimetic Nanocoating for Prolonged Circulation Time and Reduced Accelerated Blood Clearance
Authors: Rao Lang , Bu Lin‐Lin , Xu Jun‐Hua , Cai Bo , Yu Guang‐Tao , Yu Xiaolei , He Zhaobo , Huang Qinqin , Li Andrew , Guo Shi‐Shang , Zhang Wen‐Feng , Liu Wei , Sun Zhi‐Jun , Wang Hao , Wang Tza‐Huei , Zhao Xing‐Zhong
Published: October 2015

For decades, poly(ethylene glycol) (PEG) has been widely incorporated into nanoparticles for evading immune clearance and improving the systematic circulation time. However, recent studies have reported a phenomenon known as “accelerated blood clearance (ABC)” where a second dose of PEGylated nanomaterials is rapidly cleared when given several days after the first dose. Herein, we demonstrate that natural red blood cell (RBC) membrane is a superior alternative to PEG. Biomimetic RBC membrane‐coated Fe3O4 nanoparticles (Fe3O4@RBC NPs) rely on CD47, which is a “don't eat me” marker on the RBC surface, to escape immune clearance through interactions with the signal regulatory protein‐alpha (SIRP‐α) receptor. Fe3O4@RBC NPs exhibit extended circulation time and show little change between the first and second doses, with no ABC suffered. In addition, the administration of Fe3O4@RBC NPs does not elicit immune responses on neither the cellular level (myeloid‐derived suppressor cells (MDSCs)) nor the humoral level (immunoglobulin M and G (IgM and IgG)). Finally, the in vivo toxicity of these cell membrane‐camouflaged nanoparticles is systematically investigated by blood biochemistry, hematology testing, and histology analysis. These findings are significant advancements toward solving the long‐existing clinical challenges of developing biomaterials that are able to resist both immune response and rapid clearance.
Associations of arsenic metabolites, methylation capacity, and skin lesions caused by chronic exposure to high arsenic in tube well water
Authors: Yang Linsheng , Chai Yuanqing , Yu Jiangping , Wei Binggan , Xia Yajuan , Wu Kegong , Gao Jianwei , Guo Zhiwei , Cui Na
Published: October 2015

To investigate the interaction between skin lesion status and arsenic methylation profiles, the concentrations and proportions of arsenic metabolites in urine and arsenic methylation capacities of study subjects were determined. The results showed that the mean urinary concentrations of iAs (inorganic arsenic), MMA (monomethylarsonic acid), DMA (dimethylarsinic acid), and TAs (total arsenic) were 75.65, 68.78, 265.81, and 410.24 μg/L, respectively, in the skin lesions subjects. The highest values were observed in the multiple skin lesions subjects. Higher %iAs and %MMA, and lower %DMA, PMI (primary methylation index), and SMI (secondary methylation index) were found in skin lesions subjects. The multiple skin lesions subjects had highest %iAs and %MMA, and lowest %DMA, PMI, and SMI. The prevalence of skin lesions strongly, positively correlated with arsenic levels in drinking water. The elder persons also had higher frequency of skin lesions compared with younger persons. It can be concluded that arsenic levels in drinking water significantly affected the prevalence of skin lesions. Male subjects usually had higher proportions of skin lesions when compared with female subjects. Moreover, it may be concluded that MMA was significantly related to single skin lesion, whereas DMA and iAs were associated with multiple skin lesions. It seemed that MMA had greater toxicity to hyperkeratosis, whereas DMA and iAs had higher toxicity to depigmentation or pigmentation. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 28–36, 2017.
Deep learning for sentiment analysis: successful approaches and future challenges
Authors: Tang Duyu , Qin Bing , Liu Ting
Published: October 2015

Sentiment analysis (also known as opinion mining) is an active research area in natural language processing. It aims at identifying, extracting and organizing sentiments from user generated texts in social networks, blogs or product reviews. A lot of studies in literature exploit machine learning approaches to solve sentiment analysis tasks from different perspectives in the past 15 years. Since the performance of a machine learner heavily depends on the choices of data representation, many studies devote to building powerful feature extractor with domain expert and careful engineering. Recently, deep learning approaches emerge as powerful computational models that discover intricate semantic representations of texts automatically from data without feature engineering. These approaches have improved the state‐of‐the‐art in many sentiment analysis tasks including sentiment classification of sentences/documents, sentiment extraction and sentiment lexicon learning. In this paper, we provide an overview of the successful deep learning approaches for sentiment analysis tasks, lay out the remaining challenges and provide some suggestions to address these challenges. WIREs Data Mining Knowl Discov 2015, 5:292–303. doi: 10.1002/widm.1171

This article is categorized under:

Algorithmic Development > Text Mining

Technologies > Classification

Technologies > Machine Learning
Prp40 and early events in splice site definition
Authors: Becerra Soraya , Andrés‐León Eduardo , Prieto‐Sánchez Silvia , Hernández‐Munain Cristina , Suñé Carlos
Published: October 2015

The alternative splicing (AS) of precursor messenger RNA (pre‐mRNA) is a tightly regulated process through which introns are removed to leave the resulting exons in the mRNA appropriately aligned and ligated. The AS of pre‐mRNA is a key mechanism for increasing the complexity of proteins encoded in the genome. In humans, more than 90% of genes undergo AS, underscoring the importance of this process in RNA biogenesis. As such, AS misregulation underlies multiple human diseases. The splicing reaction is catalyzed by the spliceosome, a highly dynamic complex that assembles at or near the intron/exon boundaries and undergoes sequential conformational and compositional changes during splicing. The initial recognition of splice sites defines the exons that are going to be removed, which is a critical step in the highly regulated splicing process. Although the available lines of evidence are increasing, the molecular mechanisms governing AS, including the initial interactions occurring at intron/exon boundaries, and the factors that modulate these critical connections by functioning as a scaffold for active‐site RNAs or proteins, remain poorly understood. In this review, we summarize the major hallmarks of the initial steps in the splicing process and the role of auxiliary factors that contribute to the assembly of the spliceosomal complex. We also discuss the role of the essential yeast Prp40 protein and its mammalian homologs in the specificity of this pre‐mRNA processing event. In addition, we provide the first exhaustive phylogenetic analysis of the molecular evolution of Prp40 family members. WIREs RNA 2016, 7:17–32. doi: 10.1002/wrna.1312

This article is categorized under:

RNA Processing > Splicing Mechanisms

RNA Processing > Splicing Regulation/Alternative Splicing
Syntheses, Structures, and Magnetic Properties of Two Cobalt(II) Metal‐Organic Frameworks Based on Y‐shaped 3,5,4′‐Azobenzenetricarboxylic Acid and Different N‐donor Ligands
Authors: Yang Yu‐Ting , Tu Chang‐Zheng , Miao Jiao‐Jiao , Li Jun‐Li , Chen Guang , Yin Hong‐Ju , Cheng Fei‐Xiang
Published: October 2015

Two metal‐organic frameworks, [Co2(ABTC)(bimh)(OH)]·2H2O (1) and [Co3(ABTC)2(dimb)4]n (2) [H3ABTC = 3,4′,5‐azobenzenetricarboxylic acid, bimh = 1,1′‐(1,4‐hexanediy)bis(imidazole), dimb = 1,4‐bis(1H‐imidazol‐1‐yl)benzene], were prepared under solvothermal conditions and structurally characterized. Complex 1 demonstrates a complicated 3D (3,8)‐connected tfz‐d net with (43)2(46.617.85) topology. The framework of 2 can be classified as a rare 3D (3,6,6)‐connected net with the Schäfli symbol of (4.62)2(42.610.83)(44.610.8), and exhibits an intriguing self‐penetrating motif. Meanwhile, the thermal stabilities and magnetic properties for 1 and 2 were also probed.
Pride and Prejudice by Jane Austen
Authors: Wilson Raymond
Published: October 2015

Pride and Prejudice is an 1813 novel of manners by Jane Austen. The novel follows the character development of Elizabeth Bennet, the dynamic protagonist of the book who learns about the repercussions of hasty judgments and comes to appreciate the difference between superficial goodness and actual goodness.
Neutrophil–Lymphocyte Ratio as a Prognostic Marker for Lung Adenocarcinoma After Complete Resection
Authors: Takahashi Yusuke , Kawamura Masafumi , Hato Tai , Harada Masahiko , Matsutani Noriyuki , Horio Hirotoshi
Published: October 2015

Backgrounds

The neutrophil–lymphocyte ratio (NLR) is a simple and low‐cost index that may be a benchmark for systemic inflammatory response and antitumor immunity. The goal of the study was to investigate the prognostic value of preoperative NLR in patients with lung adenocarcinoma after complete resection.

Methods

The subjects were 361 consecutive patients with lung adenocarcinoma who underwent complete resection between 2000 and 2009. Perioperative clinical and laboratory data were evaluated retrospectively. The cohort was divided using the cut‐off value for preoperative NLR identified in receiver operating characteristic analysis. Correlations of NLR with clinicopathological characteristics and prognosis were examined.

Results

A high NLR was significantly correlated with a smoking history >10 pack‐years (p = 0.023), pathological stage II or III (p < 0.001), lymphatic invasion (p = 0.003), and pleural invasion (p = 0.039). In univariate analysis, the high NLR group had significantly lower 5‐year overall survival (86.0 vs. 77.1 %, p < 0.001) and 5‐year recurrence‐free survival (75.1 vs. 59.9 %, p < 0.001). Multivariate analysis showed that NLR was an independent prognostic factor (hazard ratio 1.822, 95 % confidence interval 1.133–2.931, p = 0.013).

Conclusion

These results show that preoperative NLR is an independent prognostic factor in patients with lung adenocarcinoma after complete resection. NLR may reflect host immunity and systemic inflammation that facilitates tumor growth.
Quantitative relationship between the mRNA secondary structure of translational initiation region and the expression level of heterologous protein in Escherichia coli
Authors: Yin Jun , Bao Lichen , Tian Hong , Gao Xiangdong , Yao Wenbing
Published: October 2015

Translational efficiency in Escherichia coli is strongly influenced by mRNA secondary structure of translational initiation region (TIR). We have previously reported that the expression of heterologous protein is directly related to the minimal folding free energy (ΔG) of the local secondary structure. However, identifying biologically relevant maximum and minimum levels of expression, or exploring the optimal level between them, is a key to successful optimization of heterologous protein expression. To systematically search a large range of the ΔG of TIR, we now present a quantitative analysis of the relationship between expression level and these ΔGs. The ΔG of TIR in green fluorescent protein is found to be linearly correlated with the fluorescence intensity over a range of tenfold change. The result demonstrates that the increasing ΔG of TIR can enhance the expression level linearly with no threshold or plateau.
Reaching a decision to change vocation: a qualitative study of former priests’ experiences
Authors: Pietkiewicz Igor J.
Published: October 2015

The aim of this study was to explore experiences of Roman Catholic clergy who relinquish the priesthood. Ten former priests participated in semi-structured interviews that were subjected to interpretative phenomenological analysis. Overall, the study found that priests experienced needs and aspirations conflicting with their social role and the expectations made of them. They found making decisions about vocational change frustrating and stressful because of concerns about breaking community norms, fear of social stigma, and disbelief in their ability to cope in lay life. Specific guidelines for supporting priests through counseling psychologists are provided.
The role of retinal light induced dipole in halorhodopsin structural alteration
Authors: Dutta Sansa , Hirshfeld Amiram , Sheves Mordechai
Published: October 2015

The present work studies the mechanism of light induced protein conformational changes in the over‐expressed mutant of halorhodopsin (phR) from Natronomonas pharaonis. The catalytic effect of light is reflected in accelerating hydroxyl amine reaction rate of light adapted phR. Light catalysis was detected in native phR but also in artificial pigments derived from tailored retinal analogs locked at the crucial C13=C14 double bond. It is proposed that the photoexcited retinal chromophore induces protein concerted motion that decreases the energy gap between reactants ground and transition states. This energy gap is overcome by coupling to specific protein vibrations. Surprisingly, the rate constants show unusual decreasing trend following temperature increase both for native and artificial pigments.
Systemic control of protein synthesis through sequestration of translation and ribosome biogenesis factors during severe heat stress
Authors: Cherkasov Valeria , Grousl Tomas , Theer Patrick , Vainshtein Yevhen , Gläßer Christine , Mongis Cyril , Kramer Günter , Stoecklin Georg , Knop Michael , Mogk Axel , Bukau Bernd
Published: October 2015

Environmental stress causes the sequestration of proteins into insoluble deposits including cytoplasmic stress granules (SGs), containing mRNA and a variety of translation factors. Here we systematically identified proteins sequestered in Saccharomyces cerevisiae at 46 °C by a SG co‐localization screen and proteomic analysis of insoluble protein fractions. We identified novel SG components including essential aminoacyl‐tRNA synthetases. Moreover, we discovered nucleus‐associated deposits containing ribosome biogenesis factors. Our study suggests downregulation of cytosolic protein synthesis and nuclear ribosome production at multiple levels through heat shock induced protein sequestrations.
Defects in neural guidepost structures and failure to remove leptomeningeal cells from the septal midline behind the interhemispheric fusion defects in Netrin1 deficient mice
Authors: Hakanen Janne , Salminen Marjo
Published: October 2015

Corpus callosum (CC) is the largest commissural tract in mammalian brain and it acts to coordinate information between the two cerebral hemispheres. During brain development CC forms at the boundary area between the cortex and the septum and special transient neural and glial guidepost structures in this area are thought to be critical for CC formation. In addition, it is thought that the fusion of the two hemispheres in the septum area is a prerequisite for CC formation. However, very little is known of the molecular mechanisms behind the fusion of the two hemispheres. Netrin1 (NTN1) acts as an axon guidance molecule in the developing central nervous system and Ntn1 deficiency leads to the agenesis of CC in mouse. Here we have analyzed Ntn1 deficient mice to better understand the reasons behind the observed lack of CC. We show that Ntn1 deficiency leads to defects in neural, but not in glial guidepost structures that may contribute to the agenesis of CC. In addition, Nnt1 was expressed by the leptomeningeal cells bordering the two septal walls prior to fusion. Normally these cells are removed when the septal fusion occurs. At the same time, the Laminin containing basal lamina produced by the leptomeningeal cells is disrupted in the midline area to allow the cells to mix and the callosal axons to cross. In Ntn1 deficient embryos however, the leptomeninges and the basal lamina were not removed properly from the midline area and the septal fusion did not occur. Thus, NTN1 contributes to the formation of the CC by promoting the preceding removal of the midline leptomeningeal cells and interhemispheric fusion.
A systematic review and meta‐analysis of progestogen use for maintenance tocolysis after preterm labor in women with intact membranes
Authors: Eke Ahizechukwu C. , Chalaan Tina , Shukr Ghadear , Eleje George U. , Okafor Charles I.
Published: October 2015

Background

The use of progestogens for maintenance tocolysis remains controversial, with randomized controlled trials having conflicting results on their efficacy.

Objectives

To evaluate the use of progestational agents for maintenance tocolysis after preterm labor in a systematic review of randomized controlled trials.

Search strategy

Electronic databases were searched for reports published before December 2014. Keywords included “tocolysis,” “progesterone,” “preterm labor,” “17‐alpha‐hydroxyprogesterone,” and “vaginal progesterone.”

Selection criteria

Only randomized controlled trials involving progestational agents for maintenance tocolysis were included.

Data collection and analysis

Outcomes were analyzed on an intent‐to‐treat basis and meta‐analysis was performed where appropriate. Relative risks and mean differences with 95% confidence intervals were calculated.

Main results

Four studies (362 women) were included. There were no significant differences between progestational agents and placebo/no treatment in terms of delivery before 34 weeks or before 37 weeks of pregnancy, time from randomization to delivery, and respiratory distress syndrome. Progestogens were associated with an increase in the neonatal birth weight (mean difference 203.32 g, 95% confidence interval 110.85–295.80; P = 0.032).

Conclusions

The current evidence does not support the routine use of progestational agents for maintenance tocolysis after an episode of preterm labor.
Harnessing adaptive natural killer cells in cancer immunotherapy
Authors: Liu Lisa L. , Pfefferle Aline , Yi Sheng Vincent Oei , Björklund Andreas T. , Béziat Vivien , Goodridge Jodie P. , Malmberg Karl-Johan
Published: October 2015

Natural killer (NK) cells are innate lymphocytes with a refined ability to recognize transformed cells through a broad array of activating receptors in combination with stochastically expressed inhibitory receptors that recognize MHC‐class I. Recent advances in NK cell biology have revealed a high degree of functional plasticity that can be attributed to dynamic cell‐to‐cell interactions in concert with transcriptional and epigenetic reprogramming. Here, we discuss how new insights into the adaptive behavior of NK cells pave the way for next generation cell therapy based on guided differentiation and selective expansion of particularly cytotoxic NK cell subsets.
The canonical Wnt pathway regulates the metastasis‐promoting mucin MUC4 in pancreatic ductal adenocarcinoma
Authors: Pai Priya , Rachagani Satyanarayana , Lakshmanan Imayavaramban , Macha Muzafar A. , Sheinin Yuri , Smith Lynette M. , Ponnusamy Moorthy P. , Batra Surinder K.
Published: October 2015

Aberrant Wnt signaling frequently occurs in pancreatic cancer (PC) and contributes to disease progression/metastases. Likewise, the transmembrane‐mucin MUC4 is expressed de novo in early pancreatic intraepithelial neoplasia (PanINs) and incrementally increases with PC progression, contributing to metastasis. To determine the mechanism of MUC4 upregulation in PC, we examined factors deregulated in early PC progression, such as Wnt/β‐catenin signaling. MUC4 promoter analysis revealed the presence of three putative TCF/LEF‐binding sites, leading us to hypothesize that MUC4 can be regulated by β‐catenin. Immunohistochemical (IHC) analysis of rapid autopsy PC tissues showed a correlation between MUC4 and cytosolic/nuclear β‐catenin expression. Knock down (KD) of β‐catenin in CD18/HPAF and T3M4 cell lines resulted in decreased MUC4 transcript and protein. Three MUC4 promoter luciferase constructs, p3778, p3000, and p2700, were generated. The construct p3778, encompassing the entire MUC4 promoter, elicited increased luciferase activity in the presence of stabilized β‐catenin. Mutation of the TCF/LEF site closest to the transcription start site (i.e., −2629/−2612) and furthest from the start site (i.e., −3425/−3408) reduced MUC4 promoter luciferase activity. Transfection with dominant negative TCF4 decreased MUC4 transcript and protein levels. Chromatin immunoprecipitation confirmed enrichment of β‐catenin on −2629/−2612 and −3425/−3408 of the MUC4 promoter in CD18/HPAF. Functionally, CD18/HPAF and T3M4 β‐catenin KD cells showed decreased migration and decreased Vimentin, N‐cadherin, and pERK1/2 expression. Tumorigenicity studies in athymic nude mice showed CD18/HPAF β‐catenin KD cells significantly reduced primary tumor sizes and metastases compared to scrambled control cells. We show for the first time that β‐catenin directly governs MUC4 in PC.
T‐cell receptor gene therapy — ready to go viral?
Authors: Karpanen Terhi , Olweus Johanna
Published: October 2015

T lymphocytes can be redirected to recognize a tumor target and harnessed to combat cancer by genetic introduction of T‐cell receptors of a defined specificity. This approach has recently mediated encouraging clinical responses in patients with cancers previously regarded as incurable. However, despite the great promise, T‐cell receptor gene therapy still faces a multitude of obstacles. Identification of epitopes that enable effective targeting of all the cells in a heterogeneous tumor while sparing normal tissues remains perhaps the most demanding challenge. Experience from clinical trials has revealed the dangers associated with T‐cell receptor gene therapy and highlighted the need for reliable preclinical methods to identify potentially hazardous recognition of both intended and unintended epitopes in healthy tissues. Procedures for manufacturing large and highly potent T‐cell populations can be optimized to enhance their antitumor efficacy. Here, we review the current knowledge gained from preclinical models and clinical trials using adoptive transfer of T‐cell receptor‐engineered T lymphocytes, discuss the major challenges involved and highlight potential strategies to increase the safety and efficacy to make T‐cell receptor gene therapy a standard‐of‐care for large patient groups.
Combined treatment with memantine and galantamine‐CR compared with galantamine‐CR only in antidementia drug naïve patients with mild‐to‐moderate Alzheimer's disease
Authors: Peters Oliver , Fuentes Manuel , Joachim Lisa Katharina , Jessen Frank , Luckhaus Christian , Kornhuber Johannes , Pantel Johannes , Hüll Michael , Schmidtke Klaus , Rüther Eckart , Möller Hans‐Jürgen , Kurz Alexander , Wiltfang Jens , Maier Wolfgang , Wiese Birgitt , Frölich Lutz , Heuser Isabella
Published: October 2015

Introduction

Several studies have tested the N‐methyl‐D‐aspartate–receptor antagonist memantine as an add‐on to pre‐existing treatment with acetylcholinesterase inhibitors. The objective of this study was to evaluate the efficacy and safety of a combined memantine and galantamine‐CR de novo regimen compared with galantamine‐CR only treatment in never treated patients with mild‐to‐moderate Alzheimer's disease (AD).

Methods

Antidementia drug–naïve participants (n = 232) with probable, mild‐to‐moderate AD, and mini‐mental state examination scores between 15 and 26 (inclusive) were randomized to receive either 20 mg/day memantine plus 24 mg/day galantamine‐CR or 24 mg/day galantamine‐CR plus placebo in a 52‐week, prospective, double‐blind, controlled trial. The primary outcome measurement was the change on the Alzheimer's disease assessment scale‐cognition score. Secondary measures comprised the Alzheimer's Disease Cooperative Study‐activities of daily living inventory and the clinical dementia rating.

Results

At the end of the trial, there were no statistically significant differences between the galantamine‐CR/memantine combination and galantamine‐CR only group in primary and secondary outcome measurements. The incidence and the severity of adverse events were similar between the groups.

Discussion

In this trial, memantine in combination with galantamine‐CR did not show an advantage with respect to cognition, function, and behavior in previously never treated patients with mild‐to‐moderate AD. There were no significant differences in tolerability and safety between the groups. Thus, a de novo combination treatment results in no significant improvement in disease progression (current controlled trials number: NCT01921972).
Effects of phenol on metabolic activities and transcription profiles of cytochrome P450 enzymes inChironomus kiinensislarvae
Authors: Cao C.W. , Sun L.L. , Niu F. , Liu P. , Chu D. , Wang Z.Y.
Published: October 2015

Phenol, also known as carbolic acid or phenic acid, is a priority pollutant in aquatic ecosystems. The present study has investigated metabolic activities and transcription profiles of cytochrome P450 enzymes inChironomus kiinensisunder phenol stress. Exposure ofC. kiinensislarvae to three sublethal doses of phenol (1, 10 and 100 µM) inhibited cytochrome P450 enzyme activity during the 96 h exposure period. The P450 activity measured after the 24 h exposure to phenol stress could be used to assess the level (low or high) of phenol contamination in the environment. To investigate the potential of cytochrome P450 genes as molecular biomarkers to monitor phenol contamination, the cDNA of ten CYP6 genes from the transcriptome ofC. kiinensiswere identified and sequenced. The open reading frames of the CYP6 genes ranged from 1266 to 1587 bp, encoding deduced polypeptides composed of between 421 and 528 amino acids, with predicted molecular masses from 49.01 to 61.94 kDa and isoelectric points (PI) from 6.01 to 8.89. Among the CYP6 genes, the mRNA expression levels of theCYP6EW3, CYP6EV9, CYP6FV1andCYP6FV2genes significantly altered in response to phenol exposure; therefore, these genes could potentially serve as biomarkers in the environment. This study shows that P450 activity combined with one or multipleCYP6genes could be used to monitor phenol pollution.
Dual congenital transmission ofToxoplasma gondiiandSarcocystis neuronain a late-term aborted pup from a chronically infected southern sea otter (Enhydra lutris nereis)
Authors: SHAPIRO KAREN , MILLER MELISSA A. , PACKHAM ANDREA E. , AGUILAR BEATRIZ , CONRAD PATRICIA A. , VANWORMER ELIZABETH , MURRAY MICHAEL J.
Published: October 2015

Toxoplasma gondiiandSarcocystis neuronaare protozoan parasites with terrestrial definitive hosts, and both pathogens can cause fatal disease in a wide range of marine animals. Close monitoring of threatened southern sea otters (Enhydra lutris nereis) in California allowed for the diagnosis of dual transplacental transmission ofT. gondiiandS. neuronain a wild female otter that was chronically infected with both parasites. Congenital infection resulted in late-term abortion due to disseminated toxoplasmosis.Toxoplasma gondiiandS. neuronaDNA was amplified from placental tissue culture, as well as from fetal lung tissue. Molecular characterization ofT. gondiirevealed a Type X genotype in isolates derived from placenta and fetal brain, as well as in all tested fetal organs (brain, lung, spleen, liver and thymus). This report provides the first evidence for transplacental transmission ofT. gondiiin a chronically infected wild sea otter, and the first molecular and immunohistochemical confirmation of concurrent transplacental transmission ofT. gondiiandS. neuronain any species. Repeated fetal and/or neonatal losses in the sea otter dam also suggested thatT. gondiihas the potential to reduce fecundity in chronically infected marine mammals through parasite recrudescence and repeated fetal infection.
Characterizing social environment's association with neurocognition using census and crime data linked to the Philadelphia Neurodevelopmental Cohort
Authors: Moore T. M. , Martin I. K. , Gur O. M. , Jackson C. T. , Scott J. C. , Calkins M. E. , Ruparel K. , Port A. M. , Nivar I. , Krinsky H. D. , Gur R. E. , Gur R. C.
Published: October 2015

Background

The contribution of ‘environment’ has been investigated across diverse and multiple domains related to health. However, in the context of large-scale genomic studies the focus has been on obtaining individual-level endophenotypes with environment left for future decomposition. Geo-social research has indicated that environment-level variables can be reduced, and these composites can then be used with other variables as intuitive, precise representations of environment in research.

Method

Using a large community sample (N = 9498) from the Philadelphia area, participant addresses were linked to 2010 census and crime data. These were then factor analyzed (exploratory factor analysis; EFA) to arrive at social and criminal dimensions of participants' environments. These were used to calculate environment-level scores, which were merged with individual-level variables. We estimated an exploratory multilevel structural equation model (MSEM) exploring associations among environment- and individual-level variables in diverse communities.

Results

The EFAs revealed that census data was best represented by two factors, one socioeconomic status and one household/language. Crime data was best represented by a single crime factor. The MSEM variables had good fit (e.g. comparative fit index = 0.98), and revealed that environment had the largest association with neurocognitive performance (β = 0.41, p < 0.0005), followed by parent education (β = 0.23, p < 0.0005).

Conclusions

Environment-level variables can be combined to create factor scores or composites for use in larger statistical models. Our results are consistent with literature indicating that individual-level socio-demographic characteristics (e.g. race and gender) and aspects of familial social capital (e.g. parental education) have statistical relationships with neurocognitive performance.
Aphrodite Philommêdês in the Theogony
Authors: Bouchard Elsa
Published: October 2015

Discussion of Aphrodite’s epithet philommeidês/philommêdês in Hesiod Theogony 200. Hesiod’s aetiological account of this name suggests the meaning ‘wiles-loving’ as well as ‘genitals-loving’. This interpretation is supported by a number of episodes from Archaic poetry in which literary or mythical figures make use of a ruse to permit the fulfilment of their erotic longing, or conversely exploit someone else’s desire as a means to achieve supremacy in a power struggle.
One Health approach to controlling a Q fever outbreak on an Australian goat farm
Authors: BOND K. A. , VINCENT G. , WILKS C. R. , FRANKLIN L. , SUTTON B. , STENOS J. , COWAN R. , LIM K. , ATHAN E. , HARRIS O. , MACFARLANE-BERRY L. , SEGAL Y. , FIRESTONE S. M.
Published: October 2015

A recent outbreak of Q fever was linked to an intensive goat and sheep dairy farm in Victoria, Australia, 2012-2014. Seventeen employees and one family member were confirmed with Q fever over a 28-month period, including two culture-positive cases. The outbreak investigation and management involved a One Health approach with representation from human, animal, environmental and public health. Seroprevalence in non-pregnant milking goats was 15% [95% confidence interval (CI) 7–27]; active infection was confirmed by positive quantitative PCR on several animal specimens. Genotyping ofCoxiella burnetiiDNA obtained from goat and human specimens was identical by two typing methods. A number of farming practices probably contributed to the outbreak, with similar precipitating factors to the Netherlands outbreak, 2007-2012. Compared to workers in a high-efficiency particulate arrestance (HEPA) filtered factory, administrative staff in an unfiltered adjoining office and those regularly handling goats and kids had 5·49 (95% CI 1·29–23·4) and 5·65 (95% CI 1·09–29·3) times the risk of infection, respectively; suggesting factory workers were protected from windborne spread of organisms. Reduction in the incidence of human cases was achieved through an intensive human vaccination programme plus environmental and biosecurity interventions. Subsequent non-occupational acquisition of Q fever in the spouse of an employee, indicates that infection remains endemic in the goat herd, and remains a challenge to manage without source control.
Murine models provide insight to the development of non-alcoholic fatty liver disease
Authors: Reid D. T. , Eksteen B.
Published: October 2015

Associated with the obesity epidemic, non-alcoholic fatty liver disease (NAFLD) has become the leading liver disease in North America. Approximately 30 % of patients with NAFLD may develop non-alcoholic steatohepatitis (NASH) that can lead to cirrhosis and hepatocellular carcinoma (HCC). Frequently animal models are used to help identify underlying factors contributing to NAFLD including insulin resistance, dysregulated lipid metabolism and mitochondrial stress. However, studying the inflammatory, progressive nature of NASH in the context of obesity has proven to be a challenge in mice. Although the development of effective treatment strategies for NAFLD and NASH is gaining momentum, the field is hindered by a lack of a concise animal model that reflects the development of liver disease during obesity and the metabolic syndrome. Therefore, selecting an animal model to study NAFLD or NASH must be done carefully to ensure the optimal application. The most widely used animal models have been reviewed highlighting their advantages and disadvantages to studying NAFLD and NASH specifically in the context of obesity.
Characteristics of exceptional responders to lenalidomide-based therapy in multiple myeloma
Authors: Vu T , Gonsalves W , Kumar S , Dispenzieri A , Lacy M Q , Buadi F , Gertz M A , Rajkumar S V
Published: October 2015

We studied all patients at our institution with a diagnosis of multiple myeloma (MM), from 1 January 2004 to 1 July 2009, who received lenalidomide–dexamethasone (Rd) as initial therapy and had a time to progression of 72 months or longer. Of 240 patients, we identified 33 exceptional responders. Twenty-five patients received primary therapy with Rd and eight patients received Rd induction followed by early stem cell transplantation (SCT). Seven of the eight patients who received SCT did not receive maintenance therapy; one patient received 9 months of lenalidomide post transplant. Fifteen (45%) patients had known clonal plasma cell disorder before the diagnosis of MM. The dominant mode of clinical presentation was with lytic lesions in 28 patients. Of those with informative cytogenetics (n=24), trisomies were present in 19 (79%), including one patient with concurrent trisomies and t(11;14). Overall, 21 of 24 patients (88%) had either trisomies or t(11;14). None of these exceptional responders had high-risk cytogenetic features at baseline. Twenty-five patients (76%) had a complete response (CR), whereas eight patients (24%) achieved the exceptional response state without ever achieving a CR. We identify a cohort of exceptional responders to Rd-based therapy, representing ~10–15% newly diagnosed MM patients with normal renal function.
Effects of low temperature on tropical and temperate isolates of marine Synechococcus
Authors: Varkey Deepa , Mazard Sophie , Ostrowski Martin , Tetu Sasha G , Haynes Paul , Paulsen Ian T
Published: October 2015

Temperature is an important factor influencing the distribution of marine picocyanobacteria. However, molecular responses contributing to temperature preferences are poorly understood in these important primary producers. We compared the temperature acclimation of a tropical Synechococcus strain WH8102 with temperate strain BL107 at 18 °C relative to 22 °C and examined their global protein expression, growth patterns, photosynthetic efficiency and lipid composition. Global protein expression profiles demonstrate the partitioning of the proteome into major categories: photosynthesis (>40%), translation (10–15%) and membrane transport (2–8%) with distinct differences between and within strains grown at different temperatures. At low temperature, growth and photosynthesis of strain WH8102 was significantly decreased, while BL107 was largely unaffected. There was an increased abundance of proteins involved in protein biosynthesis at 18 °C for BL107. Each strain showed distinct differences in lipid composition with higher unsaturation in strain BL107. We hypothesize that differences in membrane fluidity, abundance of protein biosynthesis machinery and the maintenance of photosynthesis efficiency contribute to the acclimation of strain BL107 to low temperature. Additional proteins unique to BL107 may also contribute to this strain’s improved fitness at low temperature. Such adaptive capacities are likely important factors favoring growth of temperate strains over tropical strains in high latitude niches.