bluuebunny/crossref_metadata_2025 huggingface dataset:
The development of the ICIQ‐UAB: A patient reported outcome measure for underactive bladder
Authors: Uren Alan D. , Cotterill Nikki , Harding Christopher , Hillary Christopher , Chapple Christopher , Lasch Kathryn , Stroupe Angela , Deshpande Chinmay , Delbecque Laure , Van Koeveringe Gommert , Oelke Matthias , Belal Mohammed , Bosch Ruud , Blok Bertil , Nitti Victor , Gotoh Momokazu , Takei Mineo , Crawford Bruce , Klaver Monique , Bongaerts Dominique , Hakimi Zalmai , Kos Ton , Abrams Paul
Published: February 2019

Aims

To present the development of the International Consultation on Incontinence Questionnaire‐underactive bladder (ICIQ‐UAB) as the first patient reported outcome measure for the assessment of the symptoms and impact on the health‐related quality of life of UAB developed in‐line with the Food and Drug Administration Guidance for Industry.

Methods

Draft items were developed following 44 semi‐structured concept elicitation interviews in the UK and refined using 36 cognitive interviews. A pilot study was designed to assess the draft ICIQ‐UAB's initial psychometric properties with 54 patients recruited from European hospitals. Further concept elicitation interviews were also carried out with 11 patients in the US and 10 patients in Japan. All participants had a prior urodynamic diagnosis of detrusor underactivity.

Results

The cognitive interviews confirmed the initial items to be understood and interpreted as intended. Pilot testing showed that both internal consistency (Cronbach's α ≥ 0.85) and test‐retest reliability (stable patients; intraclass correlation coefficient ≥ 0.88) were high. The interviews in the US and Japan elicited symptoms and impacts that support previous findings in the UK and provided further insight into the experiences of patients in those countries. The developmental ICIQ‐UAB was refined using the evidence from all substudies.

Conclusions

The validity and reliability of the ICIQ‐UAB were supported in a pilot study setting and the wider cultural applicability by the additional interviews in the US and Japan. Following further validation in future clinical trials, the developmental ICIQ‐UAB is envisaged as an important tool for the monitoring of future UAB treatment strategies.
Incidence, clinical distribution, and patient characteristics of childhood cancer in Saudi Arabia: A population‐based analysis
Authors: Belgaumi Asim F. , Pathan Ghulam Q. , Siddiqui Khawar , Ali Afshan A. , Al‐Fawaz Ibrahim , Al‐Sweedan Suleimman , Ayas Mouhab , Al‐Kofide Amani A.
Published: February 2019

Purpose

Information regarding the incidence and patterns of childhood malignancies is disproportionately overrepresented by high‐income countries, representing mainly the Caucasian population. There is a need to evaluate and disseminate information for other ethnicities, particularly from the Middle East.

Methods

Data from the National Cancer Registry, Saudi Arabia (SA‐NCR), for pediatric patients (age 0–14 years) diagnosed between 2005 and 2009 and for similar patients at our institution during the same period were analyzed. Population numbers reported in the 2007 national census were used to calculate the annual incidence of childhood cancer.

Results

Data from SA‐NCR on 3885 patients were included in this analysis. The median age was 5.58 years, and 57.3% were males. The annual age‐specific cancer incidence rate (ASR) for children in SA is 99.83 per million population; ASR per million for lymphoid leukemia is 25.75, 12.05 for brain tumors, and 9.82 for Hodgkin lymphoma. Of all childhood cancers in SA, 35% were treated at our institution. The five‐year overall survival for these 1350 patients is 74.6% (median follow‐up 7.52 years [95% confidence interval: 7.36–7.68]). Significant differences in the distribution of childhood malignancy subtypes were evident compared with other countries.

Conclusion

We have reported differences in the cancer ASR and cancer subtype distribution for children in SA as compared with the worldwide incidence and with other populations. This paper provides a comprehensive epidemiological overview of childhood cancer in SA, which could be extrapolated to other regional Arab populations.
Ultrasound Measures of the Abdominal Wall in Patients with Low Back Pain Before and After an 8‐week Lumbar Stabilization Exercise Program, and Their Association With Clinical Outcomes
Authors: Larivière Christian , Henry Sharon M. , Gagnon Dany H. , Preuss Richard , Dumas Jean‐Pierre
Published: February 2019

Background

Lumbar stabilization exercise programs (LSEPs) act positively on clinical outcome measures in patients with low back pain (LBP), but the underlying mechanisms are not well understood. Among the various neuromuscular mechanisms, a good candidate is better activation of the abdominal wall, as measured with rehabilitative ultrasound imaging (RUSI).

Objectives

To determine whether RUSI measures are (1) sensitive to LBP status and treatment (LSEP) and (2) correlate with clinical outcomes following the LSEP.

Design

An exploratory one‐arm clinical trial with healthy participants as a control group.

Setting

LSEP was delivered in a clinical setting; outcomes were measured in a laboratory setting.

Participants

Thirty‐one patients with nonacute LBP and 30 healthy controls.

Methods

Outcome measures were performed before and after an 8‐week LSEP in patients with LBP, and with the same time interval for control participants to compare with patients at baseline.

Main Outcome Measurements

Pain, disability, as well as static (at rest) and dynamic (percent thickness change) RUSI measures for abdominal muscles (transversus abdominis, internal oblique [IO], and external oblique [EO]).

Results

Patients did not produce systematic changes in RUSI measures relative to controls, even if patients had significant improvement in pain and disability. However, the correlational analyses between the absolute change (pre‐ to post‐LSEP) (1) of EO and IO thickness (in mm) at rest (bilaterally), and (2) in pain following the LSEP were significant and consistent (range: .36‐.45) in patients.

Conclusions

Although positive clinical improvements were observed following LSEP, there were minimal systematic changes in RUSI measures, likely because patients were not different from controls at baseline. Correlational analyses, however, indicated that greater reductions in pain were associated with reduced thickness of the EO and IO following the LSEP, suggesting the presence of some heterogeneity (or clinical subgroups) among the patients.

Level of Evidence

II
Milestone prediction for time‐to‐event endpoint monitoring in clinical trials
Authors: Ou Fang‐Shu , Heller Martin , Shi Qian
Published: February 2019

Predicting the times of milestone events, ie, interim and final analyses in clinical trials, helps resource planning. This manuscript presents and compares several easily implemented methods for predicting when a milestone event is achieved. We show that it is beneficial to combine the predictions from different models to craft a better predictor through prediction synthesis. Furthermore, a Bayesian approach provides a better measure of the uncertainty involved in prediction of milestone events. We compare the methods through two simulations where the model has been correctly specified and where the models are a mixture of three incorrectly specified model classes. We then apply the methods on two real clinical trial data, North Central Cancer Treatment Group (NCCTG) N0147 and N9841. In summary, the Bayesian prediction synthesis methods automatically perform well even when the data collection is far from homogeneous. AnRshiny app is under development to carry out the prediction in a user‐friendly fashion.
The analytic functional bootstrap. Part I: 1D CFTs and 2D S-matrices
Authors: Mazáč Dalimil , Paulos Miguel F.
Published: February 2019

Abstract

We study a general class of functionals providing an analytic handle on the conformal bootstrap equations in one dimension. We explicitly identify the extremal functionals, corresponding to theories saturating conformal bootstrap bounds, in two regimes. The first corresponds to functionals that annihilate the generalized free fermion spectrum. In this case, we analytically find both OPE and gap maximization functionals proving the extremality of the generalized free fermion solution to crossing. Secondly, we consider a scaling limit where all conformal dimensions become large, equivalent to the large AdS radius limit of gapped theories in AdS
2. In this regime we demonstrate analytically that optimal bounds on OPE coefficients lead to extremal solutions to crossing arising from integrable field theories placed in large AdS
2. In the process, we uncover a close connection between asymptotic extremal functionals and S-matrices of integrable field theories in flat space and explain how 2D S-matrix bootstrap results can be derived from the 1D conformal bootstrap equations. These points illustrate that our formalism is capable of capturing non-trivial solutions of CFT crossing.
Fission, fusion, and 6D RG flows
Authors: Heckman Jonathan J. , Rudelius Tom , Tomasiello Alessandro
Published: February 2019

Abstract

We show that all known 6D SCFTs can be obtained iteratively from an underlying set of UV progenitor theories through the processes of “fission” and “fusion”. Fission consists of a tensor branch deformation followed by a special class of Higgs branch deformations characterized by discrete and continuous homomorphisms into flavor symmetry algebras. Almost all 6D SCFTs can be realized as fission products. The remainder can be constructed via one step of fusion involving these fission products, whereby a single common flavor symmetry of decoupled 6D SCFTs is gauged and paired with a new tensor multiplet at the origin of moduli space, producing an RG flow “in reverse” to the UV. This leads to a streamlined labeling scheme for all known 6D SCFTs in terms of a few pieces of group theoretic data. The partial ordering of continuous homomorphisms

$$ \mathfrak{s}\mathfrak{u}(2)\to {\mathfrak{g}}_{\mathrm{flav}} $$

s
u

2

→

g
flav

for

$$ {\mathfrak{g}}_{\mathrm{flav}} $$

g
flav

a flavor symmetry also points the way to a classification of 6D RG flows.
Characterization and comparative analysis of toxin–antitoxin systems in Acetobacter pasteurianus
Authors: Xia Kai , Bao Han , Zhang Fuming , Linhardt Robert J , Liang Xinle
Published: February 2019

Bacterial toxin–antitoxin (TA) systems play important roles in diverse cellular regulatory processes. Here, we characterize three putative type II TA candidates from Acetobacter pasteurianus and investigate the profile of type II TA systems in the genus Acetobacter. Based on the gene structure and activity detection, two-pairs loci were identified as the canonical hicAB and higAB TA systems, respectively, and DB34_01190–DB34_01195 as a putative new one without a canonical TA architecture. Physiologically, the expression of the three pairs conferred E. coli with additional plasmid maintenance and survival when under acetic acid stress. Chromosomal TA systems can be horizontally transferred within an ecological vinegar microbiota by co-option, and there was a tendency for toxin module loss. The antitoxin retention in the genome is suggested to have a broad role in bacterial physiology. Furthermore, A. pasteurianus strains, universally domesticated and used for industrial vinegar fermentation, showed a higher number of type II TA loci compared to the host-associated ones. The amount of TA loci per genome showed little positive relationship to insertion sequences, although its prevalence was species-associated, to the extent of even being strain-associated. The TA system is a candidate of studying the resistant mechanistic network, the TAs-dependent translatome affords a real-time profile to explore stress adaptation of A. pasteurianus, promoting industrial development.
Comparisons of school and home-packed lunches for fruit and vegetable dietary behaviours among school-aged youths
Authors: Taylor Jennifer C , Sutter Carolyn , Ontai Lenna L , Nishina Adrienne , Zidenberg-Cherr Sheri
Published: February 2019

Objective

School-based interventions and policies encourage youths to include and consume fruits and vegetables at lunchtime via school lunches, but limited research has examined how these behaviours compare when youths have home-packed lunches. The objective of the present study was to compare fruit and vegetable contents and consumption among students having school or home-packed lunches over the school week.

Design

Participants were observed over five consecutive days at school lunchtime. Trained analysts estimated students’ lunchtime fruit and vegetable contents and consumption using digital imaging. Mixed models examined associations between fruit and vegetable dietary behaviours and lunch source (school v. home-packed), controlling for student gender, grade and school.

Setting

Three elementary schools in northern California, USA.

Participants

Fourth-, fifth- and sixth-grade students (nchildren 315; nobservations 1421).

Results

Students were significantly less likely to have and to consume fruits and vegetables (all P<0·05) when having home-packed lunches, compared with when having school lunches. Among those who did have or did consume these foods, having a home-packed lunch was associated with consuming significantly less fruit (P<0·05) but no differences for other dietary outcomes.

Conclusions

The study adds to a growing body of literature indicating shortfalls in fruit and vegetable contents and consumption associated with having a home-packed lunch, relative to having a school lunch. Findings suggest that school-based interventions, particularly when targeting home-packed lunches, should focus on whether or not these foods are included and consumed, with less emphasis on quantities.
Effect of Magnetic Storm Related Thermospheric Changes on the Evolution of Equatorial Plasma Bubbles
Authors: Bhattacharyya A. , Fedrizzi M. , Fuller‐Rowell T. J. , Gurram P. , Kakad B. , Sripathi S. , Sunda S.
Published: February 2019

Past efforts to predict scintillations on VHF and L‐band radio signals recorded at equatorial and low‐latitude stations have been mostly based on a theoretical linear growth rate of Rayleigh‐Taylor instability on the bottomside of the post‐sunset equatorial F layer, which is responsible for the generation of an equatorial plasma bubble (EPB). However, it is the maximum height that an EPB reaches above the dip equator and development of intermediate scale irregularities within the EPB, in its nonlinear phase of evolution that determines the latitudinal distribution of scintillations. Amplitude scintillations recorded by a network of VHF and L‐band receivers on a quiet day, 13 March 2015 and on 20 March 2015, a few days after the 17 March 2015 magnetic storm, show that latitudinal extent of scintillations caused by EPB irregularities is lesser on 20 March than on 13 March. Geomagnetic and ionosonde data from an equatorial station, and vertical total electron content distributions obtained from Global Navigation Satellite Systems observations, indicate that the equatorial ionospheric conditions are approximately same on these 2 days. Simulation of thermospheric conditions for these 2 days is carried out using the Coupled Thermosphere, Ionosphere, Plasmasphere, and Electrodynamics model. It is found that thermospheric atomic oxygen density is enhanced in the aftermath of the major magnetic storm of 17 March 2015, resulting in enhanced ion‐neutral collision frequencies over the dip equator on 20 March. This limits the height to which an EPB rises over the dip equator on this day, and thus impacts the latitudinal distribution of scintillations.
A Solar Signature in Many Climate Indices
Authors: Le Mouël Jean‐Louis , Lopes Fernand , Courtillot Vincent
Published: February 2019

We first apply singular spectrum analysis (SSA) to the international sunspot number (1849–2015) and the count of polar faculae (1906–2006). The SSA method finds 22‐, 11‐, and 5.5‐year components as the first eigenvectors of these solar activity proxies. We next apply SSA to the 10 Madden‐Julian oscillation (MJO; 1978–2016) indices. The first, most intense component SSA finds in all MJO indices has either a period of 5.5 or 11 years. The longer‐term modulation of amplitude is on the order of one third of the total variation. The 5.5‐year SSA component 1 of most MJO indices moreover follows the decreasing amplitude of solar cycles. We then apply SSA to climate indices Pacific Decadal Oscillation, El Nino Southern Oscillation precipitation index, Arctic Oscillation, Atlantic Multidecadal oscillation, Tropical Southern Atlantic oscillation, Western Hemisphere Warm Pool, and Brazil and Sahel rainfalls. We find that the first SSA eigenvectors are all combinations of rather pure 11, 5.5, and 3.6‐year pseudo‐cycles. The 5.5‐year component is frequently observed and is particularly important and sharp in the series in which it appears. All these periods have long been attributed to solar activity, and this by itself argues for the existence of a strong link between solar activity and climate. The mechanisms of coupling must be complex and probably nonlinear but they remain to be fully understood (UV radiation, solar wind, and galactic cosmic rays being the most promising candidates). We propose as a first step a Kuramoto model of nonlinear coupling that generates phase variations compatible with the observed ones.
Estimation of Average Diffuse Aquifer Recharge Using Time Series Modeling of Groundwater Heads
Authors: Obergfell Christophe , Bakker Mark , Maas Kees
Published: February 2019

A new method is presented to estimate average diffuse aquifer recharge of water table aquifers in temperate climates using time series analysis of water table level fluctuations. An accurate estimate of the recharge caused by rainfall requires an accurate estimate of the influence of evaporation. In temperate climates, evaporation imprints a seasonal component in the water table fluctuations. As such, recharge is estimated from time series models fitted to observed heads under the additional constraint that the seasonal harmonic of the observed head is reproduced as the sum of the transformed seasonal harmonics present in precipitation, evaporation, and pumping. An explicit equation is presented, in terms of the model parameters, for the damping and phase shift of the response to the seasonal harmonic of the stresses. Taking into account the seasonal harmonic of the observed heads results in more reliable recharge estimates compared to standard time series analysis. The method is limited to systems that are sufficiently linear and that remain unaltered over the analysis period. Head fluctuations and stresses should contain a seasonal harmonic that can be estimated with accurately. Runoff must be negligible or quantifiable. The method is applied to measured heads obtained from piezometers situated on and around the ice‐pushed sand ridge of Salland in the Netherlands and compares well with recharge estimates based on the saturated zone chloride mass balance.
Comparison of visceral fat measurement by dual-energy X-ray absorptiometry to computed tomography in HIV and non-HIV
Authors: Fourman Lindsay T. , Kileel Emma M. , Hubbard Jane , Holmes Tara , Anderson Ellen J. , Looby Sara E. , Fitch Kathleen V. , Feldpausch Meghan N. , Torriani Martin , Lo Janet , Stanley Takara L. , Grinspoon Steven K.
Published: February 2019

Background/Objectives

Individuals with HIV are susceptible to visceral fat accumulation, which confers an increased risk of cardiometabolic disease. Advanced software to ascertain visceral fat content from dual-energy X-ray absorptiometry (DXA) has not been validated among this population. We sought to compare DXA with computed tomography (CT) in the measurement of visceral fat cross-sectional area (VAT) in HIV and non-HIV using Bland–Altman analyses.

Subjects/Methods

Data were combined from five previously conducted studies of individuals with HIV (n = 313) and controls without HIV (n = 144) in which paired DXA and CT scans were available. In cross-sectional analyses, DXA-VAT was compared with CT-VAT among participants with and without HIV. In longitudinal analyses, changes in VAT over time were compared between DXA and CT among participants with and without HIV receiving no intervention over 12 months and among individuals with HIV receiving tesamorelin—a medication known to reduce VAT—over 6 months.

Results

In HIV, DXA underestimated VAT compared with CT among individuals with increased visceral adiposity. The measurement bias was −9 ± 47 cm2 overall, but became progressively larger with greater VAT (P < 0.0001), e.g., −61 ± 58 cm2 among those with VAT ≥ 200 cm2. Sex-stratified analyses revealed that the relationship between VAT and measurement bias was especially pronounced in men (P < 0.0001). Longitudinally, DXA underestimated changes in VAT, particularly among those at the extremes of VAT gain or loss (P < 0.0001). In contrast to the cross-sectional findings, the tendency for DXA to underestimate longitudinal changes in VAT was evident in both men and women. Analogous findings were seen among controls in cross-sectional and longitudinal analyses.

Conclusions

DXA underestimated VAT relative to CT in men with and without HIV, who had increased visceral adiposity. DXA also underestimated changes in VAT over time in men and women, irrespective of HIV status. DXA-VAT should be used with caution among both HIV and non-HIV-infected populations.
The prediction of suicide in severe mental illness: development and validation of a clinical prediction rule (OxMIS)
Authors: Fazel Seena , Wolf Achim , Larsson Henrik , Mallett Susan , Fanshawe Thomas R.
Published: February 2019

Assessment of suicide risk in individuals with severe mental illness is currently inconsistent, and based on clinical decision-making with or without tools developed for other purposes. We aimed to develop and validate a predictive model for suicide using data from linked population-based registers in individuals with severe mental illness. A national cohort of 75,158 Swedish individuals aged 15–65 with a diagnosis of severe mental illness (schizophrenia-spectrum disorders, and bipolar disorder) with 574,018 clinical patient episodes between 2001 and 2008, split into development (58,771 patients, 494 suicides) and external validation (16,387 patients, 139 suicides) samples. A multivariable derivation model was developed to determine the strength of pre-specified routinely collected socio-demographic and clinical risk factors, and then tested in external validation. We measured discrimination and calibration for prediction of suicide at 1 year using specified risk cut-offs. A 17-item clinical risk prediction model for suicide was developed and showed moderately good measures of discrimination (c-index 0.71) and calibration. For risk of suicide at 1 year, using a pre-specified 1% cut-off, sensitivity was 55% (95% confidence interval [CI] 47–63%) and specificity was 75% (95% CI 74–75%). Positive and negative predictive values were 2% and 99%, respectively. The model was used to generate a simple freely available web-based probability-based risk calculator (Oxford Mental Illness and Suicide tool or OxMIS) without categorical cut-offs. A scalable prediction score for suicide in individuals with severe mental illness is feasible. If validated in other samples and linked to effective interventions, using a probability score may assist clinical decision-making.
CXCR7 promotes melanoma tumorigenesis via Src kinase signaling
Authors: Xu Siran , Tang Jiaze , Wang Chunying , Liu Jie , Fu Yan , Luo Yongzhang
Published: February 2019

Chemokine receptors have been documented to exert critical functions in melanoma progression. However, current drugs targeting these receptors have limited efficacy in clinical applications, suggesting the urgency to further explore the roles of chemokine receptors in melanoma. Here we found that C–X–C chemokine receptor 7 (CXCR7) was the most highly expressed chemokine receptor in murine melanoma cell lines. In addition, the expression level of CXCR7 was positively correlated with melanoma progression in the clinical samples. High CXCR7 expression was associated with shorter overall survival in melanoma patients. Increased expression of CXCR7 augmented melanoma proliferation in vitro and tumor growth in vivo, whereas knockout of CXCR7 exhibited significant inhibitory effects. Moreover, our data elucidated that CXCR7 activated Src kinase phosphorylation in a β-arrestin2-dependent manner. The administration of the Src kinase inhibitor PP1 or siRNA specific for β-arrestin2 abolished CXCR7-promoted cell proliferation. Importantly, CXCR7 also regulated melanoma angiogenesis and the secretion of vascular endothelial growth factor (VEGF). Subsequent investigations revealed a novel event that the activation of the CXCR7-Src axis stimulated the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) to accelerate the translation of hypoxia-inducible factor 1α (HIF-1α), which enhanced the secretion of VEGF from melanoma cells. Collectively, our results illuminate the crucial roles of CXCR7 in melanoma tumorigenesis, and indicate the potential of targeting CXCR7 as new therapeutic strategies for melanoma treatment.
Publisher Correction: A meiosis-specific BRCA2 binding protein recruits recombinases to DNA double-strand breaks to ensure homologous recombination
Authors: Zhang Jingjing , Fujiwara Yasuhiro , Yamamoto Shohei , Shibuya Hiroki
Published: February 2019

The original version of this Article contained errors in Figure 5. In panel g, the male and female symbols preceding each genotype were inadvertently converted to ‘B‘ and ‘≅‘, respectively. These errors have been corrected in both the PDF and HTML versions of the Article.
Surface tension and viscosity of liquid Pd43Cu27Ni10P20 measured in a levitation device under microgravity
Authors: Mohr Markus , Wunderlich Rainer K. , Zweiacker Kai , Prades-Rödel Silke , Sauget Romuald , Blatter Andreas , Logé Roland , Dommann Alex , Neels Antonia , Johnson William L. , Fecht Hans-Jörg
Published: February 2019

Here we present measurements of surface tension and viscosity of the bulk glass-forming alloy Pd43Cu27Ni10P20 performed during containerless processing under reduced gravity. We applied the oscillating drop method in an electromagnetic levitation facility on board of parabolic flights. The measured viscosity exhibits a pronounced temperature dependence following an Arrhenius law over a temperature range from 1100 K to 1450 K. Together with literature values of viscosity at lower temperatures, the viscosity of Pd43Cu27Ni10P20 can be well described by a free volume model. X-ray diffraction analysis on the material retrieved after the parabolic flights confirm the glassy nature after vitrification of the bulk samples and thus the absence of crystallization during processing over a wide temperature range.
Synergy from gene expression and network mining (SynGeNet) method predicts synergistic drug combinations for diverse melanoma genomic subtypes
Authors: Regan-Fendt Kelly E. , Xu Jielin , DiVincenzo Mallory , Duggan Megan C. , Shakya Reena , Na Ryejung , Carson William E. , Payne Philip R. O. , Li Fuhai
Published: February 2019

Systems biology perspectives are crucial for understanding the pathophysiology of complex diseases, and therefore hold great promise for the discovery of novel treatment strategies. Drug combinations have been shown to improve durability and reduce resistance to available first-line therapies in a variety of cancers; however, traditional drug discovery approaches are prohibitively cost and labor-intensive to evaluate large-scale matrices of potential drug combinations. Computational methods are needed to efficiently model complex interactions of drug target pathways and identify mechanisms underlying drug combination synergy. In this study, we employ a computational approach, SynGeNet (Synergy from Gene expression and Network mining), which integrates transcriptomics-based connectivity mapping and network centrality analysis to analyze disease networks and predict drug combinations. As an exemplar of a disease in which combination therapies demonstrate efficacy in genomic-specific contexts, we investigate malignant melanoma. We employed SynGeNet to generate drug combination predictions for each of the four major genomic subtypes of melanoma (BRAF, NRAS, NF1, and triple wild type) using publicly available gene expression and mutation data. We validated synergistic drug combinations predicted by our method across all genomic subtypes using results from a high-throughput drug screening study across. Finally, we prospectively validated the drug combination for BRAF-mutant melanoma that was top ranked by our approach, vemurafenib (BRAF inhibitor) + tretinoin (retinoic acid receptor agonist), using both in vitro and in vivo models of BRAF-mutant melanoma and RNA-sequencing analysis of drug-treated melanoma cells to validate the predicted mechanisms. Our approach is applicable to a wide range of disease domains, and, importantly, can model disease-relevant protein subnetworks in precision medicine contexts.
A mycobacterial disease is associated with the silent mass mortality of the pen shell Pinna nobilis along the Tyrrhenian coastline of Italy
Authors: Carella F. , Aceto S. , Pollaro F. , Miccio A. , Iaria C. , Carrasco N. , Prado P. , De Vico G.
Published: February 2019

Disease is an increasing threat for marine bivalves worldwide. Recently, a mass mortality event (MME) impacting the bivalve Pinna nobilis was detected across a wide geographical area of the Spanish Mediterranean Sea and linked to a haplosporidian parasite. In 2017–2018, mass mortality events affecting the pen shell Pinna nobilis were recorded in two different regions of Italy, Campania and Sicily, in the Tyrrhenian Sea (Mediterranean Sea). Histopathological and molecular examinations of specimens showed the presence of Haplosporidium sp. in only one specimen in one area. Conversely, in all of the surveyed moribund animals, strong inflammatory lesions at the level of connective tissue surrounding the digestive system and gonads and linked to the presence of intracellular Zhiel-Neelsen-positive bacteria were observed. Molecular analysis of all of the diseased specimens (13) confirmed the presence of a Mycobacterium. Blast analysis of the sequences from all of the areas revealed that they were grouped together with the human mycobacterium M. sherrisii close to the group including M. shigaense, M. lentiflavum and M. simiae. Based on pathological and molecular findings, it is proposed that a mycobacterial disease is associated with the mortality episodes of Pinna nobilis, indicating that, at this time, Haplosporidium sp. is not responsible for these events in Campanian and Sicilian waters.
Low temperature-induced variation in plasma biochemical indices and aquaglyceroporin gene expression in the large yellow croaker Larimichthys crocea
Authors: Liu Cheng , Shen Weiliang , Hou Congcong , Gao Xinming , Wang Qianfeng , Wu Xiongfei , Zhu Junquan
Published: February 2019

Low temperature influences multiple physiological processes in fish. To explore the adaptability of the large yellow croaker (Larimichthys crocea) to low temperature, the concentrations of glycerol, blood urea nitrogen (BUN), and triglycerides (TG) in plasma, as well as the expression levels of metabolism-related genes aqp7 and aqp10, were measured after exposure to low temperature stress and during subsequent rewarming. In addition, tissue samples from the intestine and liver were histologically analyzed. We found that the concentrations of plasma glycerol, BUN, and TG, decreased under low temperature stress, suggesting the metabolism of fat and protein slowed at low temperature. The expression levels of aqp7 and aqp10 mRNA were also downregulated under exposure to low temperature. Interestingly, above plasma indices and gene expression returned to basic levels within 24 h after rewarming. Furthermore, the liver and the intestine were damaged under continuous low temperature stress, whereas they were repaired upon rewarming. From the above results, we concluded that aqp7 and aqp10 genes were sensitive to low temperature, and that the decrease in their expression levels at low temperature might reduce energy consumption by L. crocea. However, the adaptation to low temperature was limited because the key metabolic tissues were damaged under continuous exposure to low temperature. Interestingly, the metabolism of L. crocea was basically back to normal within 24 h of rewarming, showing that it has high capacity of self-recovery.
Effect of Lure Combination on Fruit Fly Surveillance Sensitivity
Authors: Stringer Lloyd D. , Soopaya Rajendra , Butler Ruth C. , Vargas Roger I. , Souder Steven K. , Jessup Andrew J. , Woods Bill , Cook Peter J. , Suckling David Maxwell
Published: February 2019

Surveillance for invading insect pests is costly and the trapper usually finds the traps empty of the target pest. Since the successful establishment of new pests is an uncommon event, multiple lures placed into one trap might increase the efficiency of the surveillance system. We investigated the effect of the combination of the Tephritidae male lures – trimedlure, cuelure, raspberry ketone and methyl eugenol – on catch of Ceratitis capitata, Zeugodacus cucurbitae, Bactrocera tryoni, B. dorsalis, B. aquilonis and B. tenuifascia in Australia and the USA (not all species are present in each country). The increase in trap density required to offset any reduction in catch due to the presence of lures for other Tephritidae was estimated. The effect of increasing trap density to maintain surveillance sensitivity was modelled for a hypothetical population of B. tryoni males, where the effective sampling area of cuelure traps for this species has been estimated. The 3-way combination significantly reduced the catch of the methyl eugenol-responsive B. dorsalis. Unexpectedly, we found that trimedlure-baited traps that contained methyl eugenol had ×3.1 lower catch of C. capitata than in trimedlure-only-baited traps in Australia, but not in Hawaii where no difference in catch was observed, we cannot satisfactorily explain this result. Based on the data presented here and from previous research, combinations of some male lures for the early detection of tephritid flies appear compatible and where there is any reduction in surveillance sensitivity observed, this can be offset by increasing the density of traps in the area.
An Archaeometric Characterization of Ecuadorian Pottery
Authors: Sánchez-Polo Alejandra , Briceño Sarah , Jamett Alex , Galeas Salomé , Campaña Orlando , Guerrero Víctor , Arroyo Carlos R. , Debut Alexis , Mowbray Duncan J. , Zamora-Ledezma Camilo , Serrano Jorge
Published: February 2019

Ecuadorian pottery is renowned for its beauty and the particularly rich colour of its pigments. However, a major challenge for art historians is the proper assessment of the provenance of individual pieces due to their lack of archaeological context. Of particular interest is the Jama-Coaque culture, which produced fascinating anthropomorphic and zoomorphic pottery from ca. 240 B.C. until the Spanish Conquest of 1532 A.D. in the coastal region of Ecuador. Using a combination of microscopic and spectroscopic techniques, i.e., transmission electron microscopy (TEM), Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), energy-dispersive x-ray spectroscopy (EDX), and scanning electron microscopy (SEM); we are able to characterize these pieces. We have found several kinds of iron-oxide based nanostructures in all the colour pigments we investigated for the Jama-Coaque culture, suggesting the same unique volcanic source material was used for their clay. Such nanostructures were absent from the pigment samples studied from other contemporary coastal-Ecuadorian cultures, i.e., the Tumaco-La Tolita and Bahía cultures. In the yellow pigments of goethite we find carbon nanofibres, indicating these pigments were subjected to a thermal treatment. Finally, in the blue, green, and black pigments we detect modern pigments (phthalocyanine blue, lithopone, and titanium white), suggesting modern restoration. Our results demonstrate the power of TEM, Raman, FTIR, EDX, and SEM archaeometric techniques for characterizing pieces without a clear archaeological context. Furthermore, the characterization of nanostructures present in such pieces could be used as a possible fingerprint for a provenance study.
The bacterial community of Quesnel Lake sediments impacted by a catastrophic mine tailings spill differ in composition from those at undisturbed locations – two years post-spill
Authors: Hatam I. , Petticrew E. L. , French T. D. , Owens P. N. , Laval B. , Baldwin S. A.
Published: February 2019

The West Basin of Quesnel Lake (British Columbia, Canada) suffered a catastrophic disturbance event in August 2014 when mine tailings and scoured natural material were deposited into the lake’s West Basin due to an impoundment failure at the adjacent Mount Polley copper-gold mine. The deposit covered a significant portion of the West Basin floor with a thick layer of material. Since lake sediments host bacterial communities that play key roles in the geochemical cycling in lacustrine environments, it is important to understand which groups inhabit the newly deposited material and what this implies for the ecological function of the West Basin. Here we report a study conducted two years post-spill, comparing the bacterial communities from sediments of both disturbed and undisturbed sites. Our results show that sediments from disturbed sites differed in physical and chemical properties than those in undisturbed sites (e.g. higher pH, particle size and Cu concentration). Furthermore, bacterial communities from the disturbed sites appeared to be legacy communities from the tailings impoundment, with metabolic potential revolving mainly around the cycling of S and metals, whereas the ones from the undisturbed sites were associated with the cycling of N.
Real-Time Forecasting of Hand-Foot-and-Mouth Disease Outbreaks using the Integrating Compartment Model and Assimilation Filtering
Authors: Zhan Zhicheng , Dong Weihua , Lu Yongmei , Yang Peng , Wang Quanyi , Jia Peng
Published: February 2019

Hand-foot-and-mouth disease (HFMD) is a highly contagious viral infection, and real-time predicting of HFMD outbreaks will facilitate the timely implementation of appropriate control measures. By integrating a susceptible-exposed-infectious-recovered (SEIR) model and an ensemble Kalman filter (EnKF) assimilation method, we developed an integrated compartment model and assimilation filtering forecast model for real-time forecasting of HFMD. When applied to HFMD outbreak data collected for 2008–11 in Beijing, China, our model successfully predicted the peak week of an outbreak three weeks before the actual arrival of the peak, with a predicted maximum infection rate of 85% or greater than the observed rate. Moreover, dominant virus types enterovirus 71 (EV-71) and coxsackievirus A16 (CV-A16) may account for the different patterns of HFMD transmission and recovery observed. The results of this study can be used to inform agencies responsible for public health management of tailored strategies for disease control efforts during HFMD outbreak seasons.
Polymeric Engineering of Nanoparticles for Highly Efficient Multifunctional Drug Delivery Systems
Authors: Fortuni Beatrice , Inose Tomoko , Ricci Monica , Fujita Yasuhiko , Van Zundert Indra , Masuhara Akito , Fron Eduard , Mizuno Hideaki , Latterini Loredana , Rocha Susana , Uji-i Hiroshi
Published: February 2019

Most targeting strategies of anticancer drug delivery systems (DDSs) rely on the surface functionalization of nanocarriers with specific ligands, which trigger the internalization in cancer cells via receptor-mediated endocytosis. The endocytosis implies the entrapment of DDSs in acidic vesicles (endosomes and lysosomes) and their eventual ejection by exocytosis. This process, intrinsic to eukaryotic cells, is one of the main drawbacks of DDSs because it reduces the drug bioavailability in the intracellular environment. The escape of DDSs from the acidic vesicles is, therefore, crucial to enhance the therapeutic performance at low drug dose. To this end, we developed a multifunctionalized DDS that combines high specificity towards cancer cells with endosomal escape capabilities. Doxorubicin-loaded mesoporous silica nanoparticles were functionalized with polyethylenimine, a polymer commonly used to induce endosomal rupture, and hyaluronic acid, which binds to CD44 receptors, overexpressed in cancer cells. We show irrefutable proof that the developed DDS can escape the endosomal pathway upon polymeric functionalization. Interestingly, the combination of the two polymers resulted in higher endosomal escape efficiency than the polyethylenimine coating alone. Hyaluronic acid additionally provides the system with cancer targeting capability and enzymatically controlled drug release. Thanks to this multifunctionality, the engineered DDS had cytotoxicity comparable to the pure drug whilst displaying high specificity towards cancer cells. The polymeric engineering here developed enhances the performance of DDS at low drug dose, holding great potential for anticancer therapeutic applications.
Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis
Authors: Yan Dingmin , Liu Xishi , Guo Sun-Wei
Published: February 2019

Endometriotic lesions are known to be hyperinnervated, especially in lesions of deep endometriosis (DE), which are frequently in close proximity to various nerve plexuses. DE lesions typically have higher fibromuscular content than that of ovarian endometriomas (OE) lesions, but the underlying reason remains elusive. Aside from their traditional role of pain transduction, however, whether or not sensory nerves play any role in the development of endometriosis is unclear. Here, we show that, thorough their respective receptors neurokinin receptor 1 (NK1R), calcitonin receptor like receptor (CRLR), and receptor activity modifying protein 1 (RAMP-1), neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) induce epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT) and further turn stromal cells into smooth muscle cells (SMCs) in endometriotic lesions, resulting ultimately in fibrosis. We show that SP and CGRP, or the rat dorsal root ganglia (DRG) supernatant, through the induction of NK1R and CGRP/CRLR/RAMP-1 signaling pathways, promoted EMT, FMT and SMM in endometriosis, resulting in increased migratory and invasive propensity, cell contractility, production of collagen, and eventually to fibrosis. Neutralization of NK1R and/or CGRP/CRLR/RAMP-1 abrogated these processes. Extended exposure of endometriotic stromal cells to SP and/or CGRP or the DRG supernatant induced increased expression of α-SMA, desmin, oxytocin receptor, and smooth muscle myosin heavy-chain. Finally, we show that DE lesions had significantly higher nerve fiber density, increased staining levels of α-SMA, NK1R, CRLR, and RAMP-1, concomitant with higher lesional fibrotic content than that of OE lesions. The extent of lesional fibrosis correlated positively with the staining levels of NK1R, CRLR, and RAMP-1, as well as the nerve fiber density in lesions. Thus, this study provides another piece of evidence that sensory nerves play an important role in promoting the development and fibrogenesis of endometriosis. It explains as why DE frequently have higher fibromuscular content than that of OE, highlights the importance of lesional microenvironment in shaping the lesional fate, gives more credence to the idea that ectopic endometrium is fundamentally wounds that go through repeated tissue injury and repair, and should shed much needed light into the pathophysiology of endometriosis.
Cholesterol bound Plasmodium falciparum co-chaperone ‘PFA0660w’ complexes with major virulence factor ‘PfEMP1’ via chaperone ‘PfHsp70-x’
Authors: Behl Ankita , Kumar Vikash , Bisht Anjali , Panda Jiban J. , Hora Rachna , Mishra Prakash Chandra
Published: February 2019

Lethality of Plasmodium falciparum caused malaria results from ‘cytoadherence’, which is mainly effected by exported Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family. Several exported P. falciparum proteins (exportome) including chaperones alongside cholesterol rich microdomains are crucial for PfEMP1 translocation to infected erythrocyte surface. An exported Hsp40 (heat shock protein 40) ‘PFA0660w’ functions as a co-chaperone of ‘PfHsp70-x’, and these co-localize to specialized intracellular mobile structures termed J-dots. Our studies attempt to understand the function of PFA0660w-PfHsp70-x chaperone pair using recombinant proteins. Biochemical assays reveal that N and C-terminal domains of PFA0660w and PfHsp70-x respectively are critical for their activity. We show the novel direct interaction of PfHsp70-x with the cytoplasmic tail of PfEMP1, and binding of PFA0660w with cholesterol. PFA0660w operates both as a chaperone and lipid binding molecule via its separate substrate and cholesterol binding sites. PfHsp70-x interacts with cholesterol bound PFA0660w and PfEMP1 simultaneously in vitro to form a complex. Collectively, our results and the past literature support the hypothesis that PFA0660w-PfHsp70-x chaperone pair assists PfEMP1 transport across the host erythrocyte through cholesterol containing ‘J-dots’. These findings further the understanding of PfEMP1 export in malaria parasites, though their in vivo validation remains to be performed.
Growth and Thermo-driven Crystalline Phase Transition of Metastable Monolayer 1T′-WSe2 Thin Film
Authors: Chen Wang , Xie Xuedong , Zong Junyu , Chen Tong , Lin Dongjin , Yu Fan , Jin Shaoen , Zhou Lingjie , Zou Jingyi , Sun Jian , Xi Xiaoxiang , Zhang Yi
Published: February 2019

Two-dimensional (2D) transition metal dichalcogenides MX2 (M = Mo, W, X = S, Se, Te) attracts enormous research interests in recent years. Its 2H phase possesses an indirect to direct bandgap transition in 2D limit, and thus shows great application potentials in optoelectronic devices. The 1T′ crystalline phase transition can drive the monolayer MX2 to be a 2D topological insulator. Here we realized the molecular beam epitaxial (MBE) growth of both the 1T′ and 2H phase monolayer WSe2 on bilayer graphene (BLG) substrate. The crystalline structures of these two phases were characterized using scanning tunneling microscopy. The monolayer 1T′-WSe2 was found to be metastable, and can transform into 2H phase under post-annealing procedure. The phase transition temperature of 1T′-WSe2 grown on BLG is lower than that of 1T′ phase grown on 2H-WSe2 layers. This thermo-driven crystalline phase transition makes the monolayer WSe2 to be an ideal platform for the controlling of topological phase transitions in 2D materials family.