bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin resistance improvement by cinnamon powder in polycystic ovary syndrome: A randomized double‐blind placebo controlled clinical trial
Authors: Hajimonfarednejad Mahdie , Nimrouzi Majid , Heydari Mojtaba , Zarshenas Mohammad Mehdi , Raee Mohammad Javad , Jahromi Bahia Namavar
Published: December 2017

Our aim is to assess the effect of cinnamon powder capsules on insulin resistance, anthropometric measurements, glucose and lipid profiles, and androgens of women with polycystic ovarian syndrome (PCOS). Out of 80 women that were diagnosed as PCOS by Rotterdam Criteria, 66 were enrolled in this randomized double‐blind placebo‐controlled clinical trial. All of the PCOS women were taking medroxy progesterone acetate 10 mg/day for the last 10 days of their menstrual cycles. The cases were randomly allocated to 2 groups. The women in the first group were treated by cinnamon powder capsules 1.5 g/day in 3 divided doses for 12 weeks and the second group by similar placebo capsules. Anthropometric measurements, fasting blood sugar, fasting insulin, blood glucose 2 hr after taking 75 g oral glucose, HbA1c, testosterone, dehydroepiandrosterone sulphate, homeostatic model assessment for insulin resistance, triglyceride, and cholesterol (low‐density lipoprotein, high‐density lipoprotein, and total) before and after the intervention were evaluated and compared as outcome measures. Fasting insulin (p = .024) and homeostatic model assessment for insulin resistance (p = .014) were reduced after 12 weeks in the cinnamon group compared with the placebo. There was also a significant decrease in low‐density lipoprotein in cinnamon group (p = .004) as compared with baseline that caused significant difference with placebo (p = .049). However, changes in other outcome measurements did not lead to statistically significant difference with placebo. The present results suggest that complementary supplementation of cinnamon significantly reduced fasting insulin and insulin resistance in women with PCOS.
Visual and tactile feedback for a direct‐manipulating tactile sensor in laparoscopic palpation
Authors: Fukuda Tomohiro , Tanaka Yoshihiro , Kappers Astrid M.L. , Fujiwara Michitaka , Sano Akihito
Published: December 2017

Background

A surgeon's tactile sense can contribute to intraoperative tumor detection, but it is limited by laparoscopic surgery.

Methods

We have developed a simple and biocompatible tactile sensor. This study aimed to design and evaluate visual and tactile feedback from the sensor for laparoscopic tumor detection. A line graph was offered through a monitor as the visual feedback. A normal force was presented to the user's foot as the tactile feedback. Twelve novices conducted a task of detecting a phantom tumor under 4 conditions (no feedback, visual feedback, tactile feedback and a combination of both types of feedback).

Results

The visual feedback was significantly more effective in detection than no feedback. Moreover, both visual and tactile feedback led to safer manipulation with significantly smaller load and lower scanning speed, respectively.

Conclusions

The results suggest that visual and tactile feedback can be useful for laparoscopic palpation; however, their effects depend on the means in which they are presented.
A Bayesian semiparametric latent variable approach to causal mediation
Authors: Kim Chanmin , Daniels Michael , Li Yisheng , Milbury Kathrin , Cohen Lorenzo
Published: December 2017

In assessing causal mediation effects in randomized studies, a challenge is that the direct and indirect effects can vary across participants due to different measured and unmeasured characteristics. In that case, the population effect estimated from standard approaches implicitly averages over and does not estimate the heterogeneous direct and indirect effects. We propose a Bayesian semiparametric method to estimate heterogeneous direct and indirect effects via clusters, where the clusters are formed by both individual covariate profiles and individual effects due to unmeasured characteristics. These cluster‐specific direct and indirect effects can be estimated through a set of regression models where specific coefficients are clustered by a stick‐breaking prior. To let clustering be appropriately informed by individual direct and indirect effects, we specify a data‐dependent prior. We conduct simulation studies to assess performance of the proposed method compared to other methods. We use this approach to estimate heterogeneous causal direct and indirect effects of an expressive writing intervention for patients with renal cell carcinoma.
Bartlett‐type corrections and bootstrap adjustments of likelihood‐based inference methods for network meta‐analysis
Authors: Noma Hisashi , Nagashima Kengo , Maruo Kazushi , Gosho Masahiko , Furukawa Toshi A.
Published: December 2017

In network meta‐analyses that synthesize direct and indirect comparison evidence concerning multiple treatments, multivariate random effects models have been routinely used for addressing between‐studies heterogeneities. Although their standard inference methods depend on large sample approximations (eg, restricted maximum likelihood estimation) for the number of trials synthesized, the numbers of trials are often moderate or small. In these situations, standard estimators cannot be expected to behave in accordance with asymptotic theory; in particular, confidence intervals cannot be assumed to exhibit their nominal coverage probabilities (also, the type I error probabilities of the corresponding tests cannot be retained). The invalidity issue may seriously influence the overall conclusions of network meta‐analyses. In this article, we develop several improved inference methods for network meta‐analyses to resolve these problems. We first introduce 2 efficient likelihood‐based inference methods, the likelihood ratio test–based and efficient score test–based methods, in a general framework of network meta‐analysis. Then, to improve the small‐sample inferences, we developed improved higher‐order asymptotic methods using Bartlett‐type corrections and bootstrap adjustment methods. The proposed methods adopt Monte Carlo approaches using parametric bootstraps to effectively circumvent complicated analytical calculations of case‐by‐case analyses and to permit flexible application to various statistical models network meta‐analyses. These methods can also be straightforwardly applied to multivariate meta‐regression analyses and to tests for the evaluation of inconsistency. In numerical evaluations via simulations, the proposed methods generally performed well compared with the ordinary restricted maximum likelihood–based inference method. Applications to 2 network meta‐analysis datasets are provided.
Investigation of 2‐stage meta‐analysis methods for joint longitudinal and time‐to‐event data through simulation and real data application
Authors: Sudell Maria , Tudur Smith Catrin , Gueyffier François , Kolamunnage‐Dona Ruwanthi
Published: December 2017

Background

Joint modelling of longitudinal and time‐to‐event data is often preferred over separate longitudinal or time‐to‐event analyses as it can account for study dropout, error in longitudinally measured covariates, and correlation between longitudinal and time‐to‐event outcomes. The joint modelling literature focuses mainly on the analysis of single studies with no methods currently available for the meta‐analysis of joint model estimates from multiple studies.

Methods

We propose a 2‐stage method for meta‐analysis of joint model estimates. These methods are applied to the INDANA dataset to combine joint model estimates of systolic blood pressure with time to death, time to myocardial infarction, and time to stroke. Results are compared to meta‐analyses of separate longitudinal or time‐to‐event models. A simulation study is conducted to contrast separate versus joint analyses over a range of scenarios.

Results

Using the real dataset, similar results were obtained by using the separate and joint analyses. However, the simulation study indicated a benefit of use of joint rather than separate methods in a meta‐analytic setting where association exists between the longitudinal and time‐to‐event outcomes.

Conclusions

Where evidence of association between longitudinal and time‐to‐event outcomes exists, results from joint models over standalone analyses should be pooled in 2‐stage meta‐analyses.
Surface Engineering of Nanoparticles for Targeted Delivery to Hepatocellular Carcinoma
Authors: Lu Jingxiong , Wang Jin , Ling Daishun
Published: December 2017

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐associated deaths worldwide. There is a lack of efficient therapy for HCC; the only available first‐line systemic drug, sorafenib, can merely improve the average survival by two months. Among the efforts to develop an efficient therapy for HCC, nanomedicine has drawn the most attention, owing to its unique features such as high drug‐loading capacity, intrinsic anticancer activities, integrated diagnostic and therapeutic functionalities, and easy surface engineering with targeting ligands. Despite its tremendous advantages, no nanomedicine can be effective unless it successfully targets the tumor site, which is a challenging task. In this review, the features of HCC are described, and the physiological hurdles that prevent nanoparticles from targeting HCC are discussed. Then, the surface physicochemical factors of nanoparticles that can influence targeting efficiency are discussed. Finally, a thorough description of the physiological barriers that nanomedicine must conquer before uptake by HCC cells if possible is provided, as well as the surface engineering approaches to nanomedicine to achieve targeted delivery to HCC cells. The physiological hurdles and corresponding solutions summarized in this review provide a general guide for the rational design of HCC targeting nanomedicine systems.
Doping of Ni and Zn Elements in MnCO3: High‐Power Anode Material for Lithium–Ion Batteries
Authors: Li Qing , Liu Zhengwang , Wang Chao , Zhao Yunhao , Che Renchao
Published: December 2017

Herein, Ni and Zn elements are doped simultaneously in MnCO3 and microspheric MnxNiyZnzCO3 is successfully obtained. Atomic mapping images reveal that the Ni and Zn elements have been successfully doped in MnCO3 and thus the prepared sample is not a mixture of MnCO3, NiCO3, and ZnCO3. It is the first time that the atomic mapping images of ternary transition metal carbonates have been demonstrated so far. The scanning transmission electron microscopy ‐ annular bright field (STEM‐ABF) image successfully confirms the formation of oxygen vacancies in MnxNiyZnzCO3, which is beneficial to improve the electrical conductivity. The evolution of the microstructure from crystal to amorphization during cycling process confirmed by the fast Fourier transform patterns effectively lowers the overpotential of the conversion reaction and accelerates the conversion between Mn2+ and much higher valence of Mn element, contributing to the superior capacity of MnxNiyZnzCO3 electrode. As anode material for lithium‐ion batteries, the prepared MnxNiyZnzCO3 exhibits excellent long‐term cycling stability and outstanding rate performance, delivering the superior reversible discharge capacities of 1066 mA h g−1 at 500 mA g−1 after 500 cycles and 760 mA h g−1 at 1 A g−1 after 1000 cycles. It is the first time that MnxNiyZnzCO3 has been synthesized and used as anode for lithium‐ion batteries so far.
‘A Considerable Degree Removed from Pauperism’?: The Social Profile of Fee-Paying Patients
Authors: Mauger Alice
Published: December 2017

Centring on patients admitted to nine selected asylums, this chapter delineates the socio-economic background of fee-paying patients. This examination is largely quantitative and draws heavily on statistics gleaned from asylum records. It charts admissions in two phases: the first to the Bloomfield Retreat and Hampstead House between 1826 and 1867, and the second to the nine asylums studied between 1868 and 1900, and explores patients’ gender, marital status, religious denomination and former occupation. The chapter reveals that many paying patients in district asylums occupied a precarious social position just above the rank of pauper. Charitable and private asylum patients, meanwhile, were usually drawn from more affluent circumstances. Exploration of patients’ social profile is supplemented by analysis of their maintenance fees and property holdings, shedding further light on the spending power of discrete social groups. The existence of an institutional marketplace is further depicted through evidence of the socio-economic overlap of patients in the three types of asylum.
Emergency‐to‐Elective Surgery Ratio: A Global Indicator of Access to Surgical Care
Authors: Prin Meghan , Guglielminotti Jean , Mtalimanja Onias , Li Guohua , Charles Anthony
Published: December 2017

Background

Surgical care is essential to health systems but remains a challenge for low‐ and middle‐income countries (LMICs). Current metrics to assess access and delivery of surgical care focus on the structural components of surgery and are not readily applicable to all settings. This study assesses a new metric for surgical care access and delivery, the ratio of emergent surgery to elective surgery (Ee ratio), which represents the number of emergency surgeries performed for every 100 elective surgeries.

Methods

A systematic search of PubMed and Medline was conducted for studies describing surgical volume and acuity published between 2006 and 2016. The relationship between Ee ratio and three national indicators (gross domestic product, per capital healthcare spending, and physician density) was analyzed using weighted Pearson correlation coefficients (rw) and linear regression models.

Results

A total of 29 studies with 33 datasets were included for analyses. The median Ee ratio was 14.6 (IQR 5.5–62.6), with a range from 1.6 to 557.4. For countries in sub‐Saharan Africa the median value was 62.6 (IQR 17.8–111.0), compared to 9.4 (IQR 3.4–13.4) for the United States and 5.5 (IQR 4.4–10.1) for European countries. In multivariable linear regression, the per capita healthcare spending was inversely associated with the Ee ratio, with a 63‐point decrease in the Ee ratio for each 1 point increase in the log of the per capita healthcare spending (regression coefficient β = −63.2; 95% CI −119.6 to −6.9; P = 0.036).

Conclusions

The Ee ratio appears to be a simple and valid indicator of access to available surgical care. Global health efforts may focus on investment in low‐resource settings to improve access to available surgical care.
Output ordering and prioritisation system (OOPS): ranking biosynthetic gene clusters to enhance bioactive metabolite discovery
Authors: Peña Alejandro , Del Carratore Francesco , Cummings Matthew , Takano Eriko , Breitling Rainer
Published: December 2017

The rapid increase of publicly available microbial genome sequences has highlighted the presence of hundreds of thousands of biosynthetic gene clusters (BGCs) encoding valuable secondary metabolites. The experimental characterization of new BGCs is extremely laborious and struggles to keep pace with the in silico identification of potential BGCs. Therefore, the prioritisation of promising candidates among computationally predicted BGCs represents a pressing need. Here, we propose an output ordering and prioritisation system (OOPS) which helps sorting identified BGCs by a wide variety of custom-weighted biological and biochemical criteria in a flexible and user-friendly interface. OOPS facilitates a judicious prioritisation of BGCs using G+C content, coding sequence length, gene number, cluster self-similarity and codon bias parameters, as well as enabling the user to rank BGCs based upon BGC type, novelty, and taxonomic distribution. Effective prioritisation of BGCs will help to reduce experimental attrition rates and improve the breadth of bioactive metabolites characterized.
CONTeMPLATE—a mnemonic to help medical educators infuse reflection into their residency curriculum
Authors: Cheung Lawrence
Published: December 2017

Reflection, where clinical experiences are analyzed to gain greater understanding and meaning, is an important step in workplace learning. Residency programs must teach their residents the skills needed for deep reflection. Medical educators may find it difficult to construct a curriculum which includes the key elements needed to enable learners to attain these skills. When we first implemented reflection into our residency curriculum, we soon realized that our curriculum only taught residents how to engage in superficial reflection. Our curriculum lacked some key elements. To help guide the transformation of our curriculum, we combed the literature for best practices. The CONTeMPLATE mnemonic was born out of this process. It is a tool to help medical educators consider and implement key elements required to enable deep reflection. The purpose of this article is to show medical educators how they can use the CONTeMPLATE mnemonic to incorporate reflective practice into their own curriculum.
Bullying victimization experiences among middle and high school adolescents: Traditional bullying, discriminatory harassment, and cybervictimization
Authors: Salmon Samantha , Turner Sarah , Taillieu Tamara , Fortier Janique , Afifi Tracie O.
Published: December 2017

The objectives of the current study were to estimate the prevalence of nine types of bullying victimization among adolescents in Grades 7 to 12, and examine how these experiences vary according to gender and school grade. Data were drawn from the Manitoba Youth Health Survey. The sample size was N = 64 174 and included boys and girls from Grades 7 to 12. Nine types of bullying victimization were assessed. Gender and grade differences were noted with girls being more to likely than boys to report six types of victimization. The odds of bullying victimization were higher in Grades 8 to 12 compared to Grade 7. Effective anti‐bullying intervention strategies need to address a range of victimization types and should consider gender and school grade. Interventions should start before Grade 7 and continue until the end of Grade 12.
Trading in Sacrifice
Authors: Stilt Kristen
Published: December 2017

The international trade of live animals, especially animals sold for slaughter, creates significant challenges for international law. Nonhuman animals do not fit neatly into the legal world created by humans. In nearly every jurisdiction, animals are property, but they are not like all other property. The sentience of animals has been widely recognized and it forms the basis of anticruelty laws where they exist. You may destroy your toaster any way you like, but the laws of most jurisdictions protect how you treat your dog. This fractured point in the law, animals as property and yet not exactly property, is the source of confusion in national laws, leading to unsatisfactory answers to questions such as what damages should be paid when a companion animal is negligently killed or whether individuals should own wildlife as “pets.”
INFLATION, INFORMATION RIGIDITY, AND THE STICKY INFORMATION PHILLIPS CURVE
Authors: Carrera César , Ramírez-Rondán N.R.
Published: December 2017

The Great Moderation is characterized as a period of stable macroeconomic conditions, especially with regard to inflation. Under the sticky information theory, this environment may provide a few incentives for agents to update information on inflation, thus, producing a new slope of the sticky information Phillips curve. We estimate the degree of information rigidity implied by the sticky information Phillips curve. Using threshold models, we identify two regimes of high and low inflation, finding that each identified regime is associated with a specific degree of information stickiness. This evidence is consistent with agents that update information faster when inflation is higher.
Product reformulation and nutritional improvements after new competitive food standards in schools
Authors: Jahn Jaquelyn L , Cohen Juliana FW , Gorski-Findling Mary T , Hoffman Jessica A , Rosenfeld Lindsay , Chaffee Ruth , Smith Lauren , Rimm Eric B
Published: December 2017

Objective

In 2012, Massachusetts enacted school competitive food and beverage standards similar to national Smart Snacks. These standards aim to improve the nutritional quality of competitive snacks. It was previously demonstrated that a majority of foods and beverages were compliant with the standards, but it was unknown whether food manufacturers reformulated products in response to the standards. The present study assessed whether products were reformulated after standards were implemented; the availability of reformulated products outside schools; and whether compliance with the standards improved the nutrient composition of competitive snacks.

Design

An observational cohort study documenting all competitive snacks sold before (2012) and after (2013 and 2014) the standards were implemented.

Setting

The sample included thirty-six school districts with both a middle and high school.

Results

After 2012, energy, saturated fat, Na and sugar decreased and fibre increased among all competitive foods. By 2013, 8 % of foods were reformulated, as were an additional 9 % by 2014. Nearly 15 % of reformulated foods were look-alike products that could not be purchased at supermarkets. Energy and Na in beverages decreased after 2012, in part facilitated by smaller package sizes.

Conclusions

Massachusetts’ law was effective in improving the nutritional content of snacks and product reformulation helped schools adhere to the law. This suggests fully implementing Smart Snacks standards may similarly improve the foods available in schools nationally. However, only some healthier reformulated foods were available outside schools.
Impacts on employment, finances, and lifestyle for working age people facing an expected premature death: A systematic review
Authors: Kochovska Slavica , Luckett Tim , Agar Meera , Phillips Jane L.
Published: December 2017

Objective:

The working ages (25–65 years) are a period when most people have significant work, financial, and family responsibilities. A small proportion of working age people will face an expected premature death from cancer or other life-limiting illness. Understanding the impact an expected premature death has on this population is important for informing support. The current study set out to summarize research describing the effects that facing an expected premature death has on employment, financial, and lifestyle of working age people and their families.

Method:

A systematic review using narrative synthesis approach. Four electronic databases were searched in July 2016 for peer-reviewed, English language studies focusing on the financial, employment, and lifestyle concerns of working age adults living with an advanced life-limiting illness and/or their carers and/or children.

Results:

Fifteen quantitative and 12 qualitative studies were included. Two-thirds (n = 18) were focused on cancer. All studies identified adverse effects on workforce participation, finances, and lifestyle. Many patients were forced to work less or give up work/retire early because of symptoms and reduced functioning. In addition to treatment costs, patients and families were also faced with child care, travel, and home/car modification costs. Being younger was associated with greater employment and financial burden, whereas having children was associated with lower functional well-being. Changes in family roles were identified as challenging regardless of diagnosis, whereas maintaining normalcy and creating stability was seen as a priority by parents with advanced cancer. This review is limited by the smaller number of studies focussing on the needs of working age people with nonmalignant disease.

Significance of results:

Working age people facing an expected premature death and their families have significant unmet financial, employment, and lifestyle needs. Comparing and contrasting their severity, timing, and priority for people with nonmalignant conditions is required to better understand their unique needs.
The Beginnings of Romanian Composition: Between Nationalism and the Obsession with Synchronizing with the West
Authors: Sandu-Dediu Valentina
Published: December 2017

Romanian composition in the nineteenth century went through rapid changes, moving from a Greek-oriental sound world to a Western European one. It is interesting to examine, in this context, the musicians’ quest for a ‘national’ sound and identity. Analysis of piano miniatures or vaudeville, the favourite genre of the Romanian audience in the first half of the century, shows eclectic combinations of urban folk music with sources of inspiration borrowed from popular foreign melodies. The second half of the century seems to be marked in modern scholarship by premieres: some composers are included in Romanian history just for the merit of writing the first Romanian symphony, the first string quartet, the first opera, and so forth. Their work led towards the constitution of a ‘national language’ adapted to genres borrowed from contemporary Western European music.

In addition to demonstrating these ideas in the work of a number of Romanian composers (Josef Herfner, Ioan Andrei Wachmann, Anton Pann, Alexandru Flechtenmacher, Ludwig Anton Wiest, Carol Miculi, George Stephănescu, Constantin Dimitrescu, Gavriil Musicescu, Eduard Caudella, George Dima, Ciprian Porumbescu, Iacob Mureşianu, Dumitru Georgescu Kiriac, Alfonso Castaldi, Eduard Wachmann), the present article also encompasses two case studies. The first is Franz Liszt’s tour through the Romanian Countries, which offers a clearer image of the popular ideas circulating within the musical scene of the time. Liszt’s initiative to emphasize the national spirit through folk quotations reworked in rhapsodies should have inspired Romanian musicians; we will see whether this actually happened. The second case study concerns the musical life of Bucharest around 1900, when the directions of Romanian modern music were being traced, and cautious and selective steps were made toward harmonizing with Europe began.
Evaluating scale and technical efficiency among farms and ranches with a local market orientation
Authors: Bauman Allison , Thilmany Dawn , Jablonski Becca B.R.
Published: December 2017

In recent years, the growth in local food marketing channels has been significant. Most of the research in this field examining the economic implication of these trends has focused post-farmgate including supply chain analysis (e.g., Hardesty et al., 2014; King et al., 2010), regional economic impacts (e.g., Brown et al., 2014; Hughes et al., 2008; Jablonski et al., 2016) and consumer values and motivations that have driven demand (e.g., Costanigro, 2014; Lusk and Briggeman, 2009). To date, with the exception of a few case studies examining expenses and sales by channel assessment (LeRoux et al., 2010; Hardesty and Leff, 2010; Jablonski and Schmit, 2016) there has been little research that examines the impact on financial viability among farms selling through these markets. The goal of this paper is twofold: first, to identify the factors that have the greatest influence on the efficiency of farmers and ranchers that participate in local food systems, and second, to estimate the relationship between marketing strategy and farm financial efficiency, with a particular focus on variations across farm size. Our estimation of the stochastic production frontier suggests that scale, production enterprise specialty, market outlet choices, land ownership, and management of expenses have the greatest influence on producer financial efficiency. Our model suggests that scale has the largest impact on financial efficiency, providing evidence that, all else constant, the most important factor in the efficiency of direct market producers is scale. When profit is defined as operating profit, results indicate that marketing channel is not an important indicator of efficiency. But when profit is defined as return on assets, marketing channel is an important indicator of efficiency, albeit less than is scale. Results from this analysis indicate there are economies of scale associated with farms and ranches that sell through local and regional markets, and that scale rather than marketing channel has the largest influence on efficiency.
RETRACTED ARTICLE: Cadherin 6 is activated by Epstein–Barr virus LMP1 to mediate EMT and metastasis as an interplay node of multiple pathways in nasopharyngeal carcinoma
Authors: Zuo L-L , Zhang J , Liu L-Z , Zhou Q , Du S-J , Xin S-Y , Ning Z-P , Yang J , Yu H-B , Yue W-X , Wang J , Zhu F-X , Li G-Y , Lu J-H
Published: December 2017

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy, which is notorious among head-and-neck cancers with its metastatic feature. Epstein–Barr virus (EBV) infection plays a fundamental role in NPC development with the mechanism is not well understood. Here we demonstrate that EBV oncoprotein LMP1 drives EMT and metastasis of NPC by reactivating the adhesion molecule, cadherin 6 (CDH6), which normally occurs in embryogenesis with unknown role in NPC. CDH6 was found to be upregulated in LMP1-positive NPC tissues, and was identified as a target of the epithelium-specific miR-203. LMP1-activated NF-κB transcriptionally repressed the miR-203 expression by binding to the promoter region of miR-203 gene. CDH6 activation in turn induced EMT and promoted metastasis in NPC. CDH6 depletion, NF-κB inhibitor and miR-203 overexpression were able to impair the EMT effects. The miR-203 downregulation in NPC tissues was strongly associated with metastasis clinically. The CDH6 activator, Runt-related transcription factor 2 (RUNX2), was also activated by EBV in the event. For both CDH6 and RUNX2 are components at TGF-β downstream, CDH6 became a node protein for the interplay of multiple signalings including NF-κB and TGF-β. Therefore, the switch-on of miR-203 was important for nasopharyngeal epithelial cells to maintain normal phenotype. This study demonstrates that EBV has evolved sophisticated strategies by driving epithelial cells to obtain malignant features, particularly in NPC metastasis, providing novel biomarkers for the therapy and prognosis of EBV-associated NPC.
Strain profiling and epidemiology of bacterial species from metagenomic sequencing
Authors: Albanese Davide , Donati Claudio
Published: December 2017

Microbial communities are often composed by complex mixtures of multiple strains of the same species, characterized by a wide genomic and phenotypic variability. Computational methods able to identify, quantify and classify the different strains present in a sample are essential to fully exploit the potential of metagenomic sequencing in microbial ecology, with applications that range from the epidemiology of infectious diseases to the characterization of the dynamics of microbial colonization. Here we present a computational approach that uses the available genomic data to reconstruct complex strain profiles from metagenomic sequencing, quantifying the abundances of the different strains and cataloging them according to the population structure of the species. We validate the method on synthetic data sets and apply it to the characterization of the strain distribution of several important bacterial species in real samples, showing how its application provides novel insights on the structure and complexity of the microbiota.
Protein conformational flexibility modulates kinetics and thermodynamics of drug binding
Authors: Amaral M. , Kokh D. B. , Bomke J. , Wegener A. , Buchstaller H. P. , Eggenweiler H. M. , Matias P. , Sirrenberg C. , Wade R. C. , Frech M.
Published: December 2017

Structure-based drug design has often been restricted by the rather static picture of protein–ligand complexes presented by crystal structures, despite the widely accepted importance of protein flexibility in biomolecular recognition. Here we report a detailed experimental and computational study of the drug target, human heat shock protein 90, to explore the contribution of protein dynamics to the binding thermodynamics and kinetics of drug-like compounds. We observe that their binding properties depend on whether the protein has a loop or a helical conformation in the binding site of the ligand-bound state. Compounds bound to the helical conformation display slow association and dissociation rates, high-affinity and high cellular efficacy, and predominantly entropically driven binding. An important entropic contribution comes from the greater flexibility of the helical relative to the loop conformation in the ligand-bound state. This unusual mechanism suggests increasing target flexibility in the bound state by ligand design as a new strategy for drug discovery.
Generic wound signals initiate regeneration in missing-tissue contexts
Authors: Owlarn Suthira , Klenner Felix , Schmidt David , Rabert Franziska , Tomasso Antonio , Reuter Hanna , Mulaw Medhanie A. , Moritz Sören , Gentile Luca , Weidinger Gilbert , Bartscherer Kerstin
Published: December 2017

Despite the identification of numerous regulators of regeneration in different animal models, a fundamental question remains: why do some wounds trigger the full regeneration of lost body parts, whereas others resolve by mere healing? By selectively inhibiting regeneration initiation, but not the formation of a wound epidermis, here we create headless planarians and finless zebrafish. Strikingly, in both missing-tissue contexts, injuries that normally do not trigger regeneration activate complete restoration of heads and fin rays. Our results demonstrate that generic wound signals have regeneration-inducing power. However, they are interpreted as regeneration triggers only in a permissive tissue context: when body parts are missing, or when tissue-resident polarity signals, such as Wnt activity in planarians, are modified. Hence, the ability to decode generic wound-induced signals as regeneration-initiating cues may be the crucial difference that distinguishes animals that regenerate from those that cannot.
Access to stereodefined (Z)-allylsilanes and (Z)-allylic alcohols via cobalt-catalyzed regioselective hydrosilylation of allenes
Authors: Wang Chao , Teo Wei Jie , Ge Shaozhong
Published: December 2017

Hydrosilylation of allenes is the addition of a hydrogen atom and a silyl group to a carbon–carbon double bond of an allene molecule and represents a straightforward and atom-economical approach to prepare synthetically versatile allylsilanes and vinylsilanes. However, this reaction generally produces six possible isomeric organosilanes, and the biggest challenge in developing this reaction is to control both regioselectivity and stereoselectivity. The majorities of the developed allene hydrosilylation reactions show high selectivity towards the production of vinylsilanes or branched allylsilanes. By employing a cobalt catalyst generated from readily available and bench-stable cobalt precursor and phosphine-based ligands, here we show that this reaction proceeds under mild conditions in a regioselective and stereoselective manner, and affords synthetically challenging, but valuable linearcis-allylsilanes with excellent stereoselectivity (generallycistotransratios: >98:2). This cobalt-catalyzed (Z)-selective allene hydrosilylation provides a general approach to access molecules containing stereodefined (Z)-alkene units.
Methylation-regulated decommissioning of multimeric PP2A complexes
Authors: Wu Cheng-Guo , Zheng Aiping , Jiang Li , Rowse Michael , Stanevich Vitali , Chen Hui , Li Yitong , Satyshur Kenneth A. , Johnson Benjamin , Gu Ting-Jia , Liu Zuojia , Xing Yongna
Published: December 2017

Dynamic assembly/disassembly of signaling complexes are crucial for cellular functions. Specialized latency and activation chaperones control the biogenesis of protein phosphatase 2A (PP2A) holoenzymes that contain a common scaffold and catalytic subunits and a variable regulatory subunit. Here we show that the butterfly-shaped TIPRL (TOR signaling pathway regulator) makes highly integrative multibranching contacts with the PP2A catalytic subunit, selective for the unmethylated tail and perturbing/inactivating the phosphatase active site. TIPRL also makes unusual wobble contacts with the scaffold subunit, allowing TIPRL, but not the overlapping regulatory subunits, to tolerate disease-associated PP2A mutations, resulting in reduced holoenzyme assembly and enhanced inactivation of mutant PP2A. Strikingly, TIPRL and the latency chaperone, α4, coordinate to disassemble active holoenzymes into latent PP2A, strictly controlled by methylation. Our study reveals a mechanism for methylation-responsive inactivation and holoenzyme disassembly, illustrating the complexity of regulation/signaling, dynamic complex disassembly, and disease mutations in cancer and intellectual disability.
Molecular understanding of polyelectrolyte binders that actively regulate ion transport in sulfur cathodes
Authors: Li Longjun , Pascal Tod A. , Connell Justin G. , Fan Frank Y. , Meckler Stephen M. , Ma Lin , Chiang Yet-Ming , Prendergast David , Helms Brett A.
Published: December 2017

Polymer binders in battery electrodes may be either active or passive. This distinction depends on whether the polymer influences charge or mass transport in the electrode. Although it is desirable to understand how to tailor the macromolecular design of a polymer to play a passive or active role, design rules are still lacking, as is a framework to assess the divergence in such behaviors. Here, we reveal the molecular-level underpinnings that distinguish an active polyelectrolyte binder designed for lithium–sulfur batteries from a passive alternative. The binder, a cationic polyelectrolyte, is shown to both facilitate lithium-ion transport through its reconfigurable network of mobile anions and restrict polysulfide diffusion from mesoporous carbon hosts by anion metathesis, which we show is selective for higher oligomers. These attributes allow cells to be operated for >100 cycles with excellent rate capability using cathodes with areal sulfur loadings up to 8.1 mg cm–2.
δ-Subunit Containing GABAA Receptors Modulate Respiratory Networks
Authors: Montandon Gaspard , Wu Haiying , Liu Hattie , Vu Michael T. , Orser Beverley A. , Horner Richard L.
Published: December 2017

Persistent and stable respiratory activity across behavioral states is key to homeostasis. Extrasynaptic δ-subunit containing GABAA receptors (δGABAARs) mediate tonic inhibition and regulate network activity. However, the influence of δGABAARs on respiratory rhythm and motor outputs is unknown. We manipulated extra-synaptic GABAA receptor function in the preBötzinger Complex (preBötC), a site central to the generation of inspiratory motor activity in mammals. Activation of preBötC δGABAARs in anesthetized rats and wild-type mice decreased breathing rate. In δGABAAR knockout (Gabrd−/−) mice, however, δGABAARs activation had no effect on breathing rate. We then found that during active wakefulness associated with behaviors and movements, diaphragm activation was higher in the Gabrd−/− compared to wild-type mice, but not in other states. These findings identify that δGABAARs modulate the respiratory network, which is critical to understand how δGABAARs change breathing in pathological conditions affecting extra-synaptic GABAA receptor function such as exposure to anesthetics and neurosteroids.
Crude phosphorylation mixtures containing racemic lipid amphiphiles self-assemble to give stable primitive compartments
Authors: Fayolle Dimitri , Altamura Emiliano , D’Onofrio Alice , Madanamothoo Warren , Fenet Bernard , Mavelli Fabio , Buchet René , Stano Pasquale , Fiore Michele , Strazewski Peter
Published: December 2017

It is an open question how the chemical structure of prebiotic vesicle-forming amphiphiles complexified to produce robust primitive compartments that could safely host foreign molecules. Previous work suggests that comparingly labile vesicles composed of plausibly prebiotic fatty acids were eventually chemically transformed with glycerol and a suitable phosphate source into phospholipids that would form robust vesicles. Here we show that phosphatidic acid (PA) and phosphatidylethanolamine (PE) lipids can be obtained from racemic dioleoyl glycerol under plausibly prebiotic phosphorylation conditions. Upon in situ hydration of the crude phosphorylation mixtures only those that contained rac-DOPA (not rac-DOPE) generated stable giant vesicles that were capable of encapsulating water-soluble probes, as evidenced by confocal microscopy and flow cytometry. Chemical reaction side-products (identified by IR and MS and quantified by 1H NMR) acted as co-surfactants and facilitated vesicle formation. To mimic the compositional variation of such primitive lipid mixtures, self-assembly of a combinatorial set of the above amphiphiles was tested, revealing that too high dioleoyl glycerol contents inhibited vesicle formation. We conclude that a decisive driving force for the gradual transition from unstable fatty acid vesicles to robust diacylglyceryl phosphate vesicles was to avoid the accumulation of unphosphorylated diacylglycerols in primitive vesicle membranes.
Hydrolytic activity determination of Tail Tubular Protein A of Klebsiella pneumoniae bacteriophages towards saccharide substrates
Authors: Brzozowska Ewa , Pyra Anna , Pawlik Krzysztof , Janik Monika , Górska Sabina , Urbańska Natalia , Drulis-Kawa Zuzanna , Gamian Andrzej
Published: December 2017

In this paper, the enzymatic activity, substrate specificity and antibiofilm feature of bacteriophage dual-function tail proteins are presented. So far, tail tubular proteins A–TTPAgp31 and TTPAgp44-have been considered as structural proteins of Klebsiella pneumoniae bacteriophages KP32 and KP34, respectively. Our results show that TTPAgp31 is able to hydrolyze maltose as well as Red-starch. The activity of 1 µM of the protein was calculated as 47.6 milli-Units/assay relating to the α-amylase activity. It degrades capsular polysaccharides (cPS), slime polysaccharides (sPS) and lipopolysaccharide (LPS) of K. pneumoniae PCM 2713 and shows antibiofilm reactivity towards S. aureus PCM 519 and E. faecalis PCM 2673. TTPAgp44 hydrolyses trehalose and cPS of E. faecium PCM 1859. TTPAgp44′s activity was also observed in the antibiofilm test against P. aeruginosa PCM 2710 and B. subtilis PCM 2021. TTPAgp31 has been identified as α-1,4-glucosidase whereas, TTPAgp44 exhibits trehalase-like activity. Both proteins contain aspartate and glutamate residues in the β-stranded region which are essential for catalytic activity of glycoside hydrolases. The significant novelty of our results is that for the first time the bacteriophage tubular proteins are described as the unique enzymes displaying no similarity to any known phage hydrolases. They can be used as antibacterial agents directed against bacterial strains producing exopolysaccharides and forming a biofilm.
Radiosensitization of Prostate Cancers In Vitro and In Vivo to Erbium-filtered Orthovoltage X-rays Using Actively Targeted Gold Nanoparticles
Authors: Khoo Allison M. , Cho Sang Hyun , Reynoso Francisco J. , Aliru Maureen , Aziz Kathryn , Bodd Monica , Yang Xi , Ahmed Md F. , Yasar Selcuk , Manohar Nivedh , Cho Jongmin , Tailor Ramesh , Thames Howard D. , Krishnan Sunil
Published: December 2017

Theoretical investigations suggest that gold nanoparticle (GNP)-mediated radiation dose enhancement and radiosensitization can be maximized when photons interact with gold, predominantly via photoelectric absorption. This makes ytterbium (Yb)-169, which emits photons with an average energy of 93 keV (just above the K-edge of gold), an ideal radioisotope for such purposes. This investigation tests the feasibility of tumor-specific prostate brachytherapy achievable with Yb-169 and actively targeted GNPs, using an external beam surrogate of Yb-169 created from an exotic filter material - erbium (Er) and a standard copper-filtered 250 kVp beam. The current in vitro study shows that treatment of prostate cancer cells with goserelin-conjugated gold nanorods (gGNRs) promotes gonadotropin releasing hormone receptor-mediated internalization and enhances radiosensitivity to both Er-filtered and standard 250 kVp beams, 14 and 10%, respectively. While the degree of GNP-mediated radiosensitization as seen from the in vitro study may be considered moderate, the current in vivo study shows that gGNR treatment plus Er-filtered x-ray irradiation is considerably more effective than radiation treatment alone (p < 0.0005), resulting in a striking reduction in tumor volume (50% smaller) 2 months following treatment. Overall, the current results provide strong evidence for the feasibility of tumor-specific prostate brachytherapy with Yb-169 and gGNRs.
Clay content and pH: soil characteristic associations with the persistent presence of chronic wasting disease in northern Illinois
Authors: Dorak Sheena J. , Green Michelle L. , Wander Michelle M. , Ruiz Marilyn O. , Buhnerkempe Michael G. , Tian Ting , Novakofski Jan E. , Mateus-Pinilla Nohra E.
Published: December 2017

Environmental reservoirs are important to infectious disease transmission and persistence, but empirical analyses are relatively few. The natural environment is a reservoir for prions that cause chronic wasting disease (CWD) and influences the risk of transmission to susceptible cervids. Soil is one environmental component demonstrated to affect prion infectivity and persistence. Here we provide the first landscape predictive model for CWD based solely on soil characteristics. We built a boosted regression tree model to predict the probability of the persistent presence of CWD in a region of northern Illinois using CWD surveillance in deer and soils data. We evaluated the outcome for possible pathways by which soil characteristics may increase the probability of CWD transmission via environmental contamination. Soil clay content and pH were the most important predictive soil characteristics of the persistent presence of CWD. The results suggest that exposure to prions in the environment is greater where percent clay is less than 18% and soil pH is greater than 6.6. These characteristics could alter availability of prions immobilized in soil and contribute to the environmental risk factors involved in the epidemiological complexity of CWD infection in natural populations of white-tailed deer.
Multiple Cryptic Binding Sites are Necessary for Robust Fibronectin Assembly: An In Silico Study
Authors: Lemmon Christopher A. , Weinberg Seth H.
Published: December 2017

The mechanism of assembly of the extracellular matrix protein fibronectin (FN) into elastic, insoluble fibrils is still poorly understood. FN fibrillogenesis requires cell-generated forces, which expose cryptic FN-FN binding sites buried in FN Type III domains. The number and location of cryptic binding sites have been debated, but experimental evidence suggests multiple domains may contain FN-FN binding sites. The requirement of cell-dependent forces to generate FN fibrils restricts investigation of the mechanism of assembly. To address this, we use a recently developed biophysical model of fibrillogenesis to test competing hypotheses for the location and number of cryptic FN-FN binding sites and quantify the effect of these molecular alterations on assembled FN fibril properties. Simulations predict that a single FN-FN binding site facilitates either negligible fibrillogenesis or produces FN fibrils that are neither robust nor physiological. However, inclusion of multiple FN-FN binding sites predicts robust fibrillogenesis, which minimally depends on individual domain properties. Multiple FN-FN binding site models predict a heterogeneous fibril population that contains two distinct phenotypes with unique viscoelastic properties, which we speculate may play a key role in generating heterogeneous mechanical signaling in the extracellular matrix of developing and regenerating tissues.