bluuebunny/crossref_metadata_2025 huggingface dataset:
Conserved DNA motifs in the type II-A CRISPR leader region
Authors: Van Orden Mason J. , Klein Peter , Babu Kesavan , Najar Fares Z. , Rajan Rakhi
Published: April 2017

The Clustered Regularly Interspaced Short Palindromic Repeats associated (CRISPR-Cas) systems consist of RNA-protein complexes that provide bacteria and archaea with sequence-specific immunity against bacteriophages, plasmids, and other mobile genetic elements. Bacteria and archaea become immune to phage or plasmid infections by inserting short pieces of the intruder DNA (spacer) site-specifically into the leader-repeat junction in a process called adaptation. Previous studies have shown that parts of the leader region, especially the 3′ end of the leader, are indispensable for adaptation. However, a comprehensive analysis of leader ends remains absent. Here, we have analyzed the leader, repeat, and Cas proteins from 167 type II-A CRISPR loci. Our results indicate two distinct conserved DNA motifs at the 3′ leader end: ATTTGAG (noted previously in the CRISPR1 locus ofStreptococcus thermophilusDGCC7710) and a newly defined CTRCGAG, associated with the CRISPR3 locus ofS. thermophilusDGCC7710. A third group with a very short CG DNA conservation at the 3′ leader end is observed mostly in lactobacilli. Analysis of the repeats and Cas proteins revealed clustering of these CRISPR components that mirrors the leader motif clustering, in agreement with the coevolution of CRISPR-Cas components. Based on our analysis of the type II-A CRISPR loci, we implicate leader end sequences that could confer site-specificity for the adaptation-machinery in the different subsets of type II-A CRISPR loci.
Lagrangian simulation of mixing and reactions in complex geochemical systems
Authors: Engdahl Nicholas B. , Benson David A. , Bolster Diogo
Published: April 2017

Simulations of detailed geochemical systems have traditionally been restricted to Eulerian reactive transport algorithms. This note introduces a Lagrangian method for modeling multicomponent reaction systems. The approach uses standard random walk‐based methods for the particle motion steps but allows the particles to interact with each other by exchanging mass of their various chemical species. The colocation density of each particle pair is used to calculate the mass transfer rate, which creates a local disequilibrium that is then relaxed back toward equilibrium using the reaction engine PhreeqcRM. The mass exchange is the only step where the particles interact and the remaining transport and reaction steps are entirely independent for each particle. Several validation examples are presented, which reproduce well‐known analytical solutions. These are followed by two demonstration examples of a competitive decay chain and an acid‐mine drainage system. The source code, entitled Complex Reaction on Particles (CRP), and files needed to run these examples are hosted openly on GitHub (https://github.com/nbengdahl/CRP), so as to enable interested readers to readily apply this approach with minimal modifications.
Visible‐Light Photocatalytic Bicyclization of 1,7‐Enynes toward Functionalized Sulfone‐Containing Benzo[a]fluoren‐5‐ones
Authors: Huang Min‐Hua , Zhu Yi‐Long , Hao Wen‐Juan , Wang Ai‐Fang , Wang De‐Cai , Liu Feng , Wei Ping , Tu Shu‐Jiang , Jiang Bo
Published: April 2017

A new visible‐light photocatalytic arylsulfonylation and bicyclization of C(sp3)‐tethered 1,7‐enynes with sulfinic acids has been developed, delivering functionalized sulfone‐containing benzo[a]fluoren‐5‐ones with generally good yields. This Eosin Y‐catalyzed approach makes use of visible light as a safe and eco‐friendly energy source to drive cascade cyclization reactions, resulting in continuous multiple bond‐forming events including C–S and C–C bonds to efficiently construct polycyclic‐linked alkyl aryl sulfones.

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Autism spectrum disorders and the amplitude of auditory brainstem response wave I
Authors: Santos Mariline , Marques Cristina , Nóbrega Pinto Ana , Fernandes Raquel , Coutinho Miguel Bebiano , Almeida e Sousa Cecília
Published: April 2017

To determine whether children with autism spectrum disorders (ASDs) have an increased number of wave I abnormal amplitudes in auditory brainstem responses (ABRs) than age‐ and sex‐matched typically developing children. This analytical case–control study compared patients with ASDs between the ages of 2 and 6 years and children who had a language delay not associated with any other pathology. Amplitudes of ABR waves I and V; absolute latencies (ALs) of waves I, III, and V; and interpeak latencies (IPLs) I–III, III–IV, and I–V at 90 dB were compared between ASD patients and normally developing children. The study enrolled 40 children with documented ASDs and 40 age‐ and sex‐matched control subjects. Analyses of the ABR showed that children with ASDs exhibited higher amplitudes of wave 1 than wave V (35%) more frequently than the control group (10%), and this difference between groups reached statistical significance by Chi‐squared analysis. There were no significant differences in ALs and IPLs between ASD children and matched controls. To the best of our knowledge, this is the first case–control study testing the amplitudes of ABR wave I in ASD children. The reported results suggest a potential for the use of ABR recordings in children, not only for the clinical assessment of hearing status, but also for the possibility of using amplitude of ABR wave I as an early marker of ASDs allowing earlier diagnosis and intervention. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 1300–1305. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.
Infants at‐risk for autism spectrum disorder: Patterns of vocalizations at 14 months
Authors: Garrido Dunia , Watson Linda R. , Carballo Gloria , Garcia‐Retamero Rocio , Crais Elizabeth R.
Published: April 2017

Differences in the early development of children are crucial for early detection of autism spectrum disorder (ASD). Previous studies have shown large differences between children later diagnosed with ASD and their typically developing peers in the early use of canonical vocalizations (i.e., vocalizations that include well‐formed consonant–vowel syllables) and the use of vocalizations for communicative purposes. In this prospective study, we examined the extent to which infant vocalizations at 14 months would predict Autism Diagnostic Observation Schedule (ADOS) diagnostic symptom groups, that is, Autism, Spectrum, and Non‐ASD, for 82 community‐identified at‐risk infants at 23 months. Thirty‐minute video samples were coded with the intention to categorize and quantify speech (canonical/noncanonical and directed/nondirected) and nonspeech vocalizations (atypical, distress, and pleasure vocalizations). Our results revealed that more canonical directed (OR = 1.039, P = .036), and fewer noncanonical directed (OR=.607, P = .002) and noncanonical nondirected (OR = 1.200, P = .049) vocalizations were associated with a greater likelihood of being in the Non‐ASD group versus the Autism group, with no variables significantly predicting Autism versus Spectrum group membership. Despite some statistically significant findings, models performed poorly in classifying children into correct ASD symptom group at age 23 months based on vocalizations at 14 months. Thus, the utility of infant vocalizations alone for predicting toddler clinical outcomes among infants initially identified at an elevated risk for ASD appears limited; however, considering the structure and function of early vocalizations combined with other early developmental and behavioral features may improve the confidence for clinicians in making an early diagnosis of ASD. Autism Res 2017, 10: 1372–1383. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.
Who studies STEM subjects at A level and degree in England? An investigation into the intersections between students’ family background, gender and ethnicity in determining choice
Authors: Codiroli Mcmaster Natasha
Published: April 2017

The relative lack of students studying post‐compulsory STEM (Science, Technology, Engineering and Mathematics) subjects is a key policy concern. A particular issue is the disparities in uptake by students’ family background, gender and ethnicity. It remains unclear whether the relationship between student characteristics and choice can be explained by academic disparities, and whether students’ background, gender and ethnicity interact in determining university subject choices, rather than simply having additive effects. I use data from more than 4000 students in England from ‘Next Steps’ (previously the LSYPE) and logistic regression methods to explore the interacting relationships between student characteristics and subject choice. There are four main findings of this study. Firstly, disparities by students’ ethnicity are shown to increase when controlling for prior attainment. Secondly, family background indicators are differentially related to uptake for male and female students, with parents’ social class and education larger predictors of choice than financial resources. Thirdly, gender, ethnicity and family background interact in determining choices. Particularly, as socio‐economic position increases, young women are more likely to choose STEM over other high‐return subjects. Finally, associations between student characteristics and subject choices, including interactions, largely persisted when accounting for A‐level choices. Implications for policy and future research are discussed.
Monitoring Reactions on Solid Phases with Raman Spectroscopy
Authors: Protasova Irina , Heißler Stefan , Jung Nicole , Bräse Stefan
Published: April 2017

The benefits of Raman spectroscopy were shown for the on‐bead monitoring of diverse reactions. Raman spectroscopy was used for the development of new procedures on established linker systems, the real‐time observation of several reactions on solid phases and the estimation of the reaction time for a new cleavage strategy. Selected conversions on solid phases, such as the on‐bead conversion of functional groups and the attachment of novel building blocks, were demonstrated. Raman spectra were obtained after isolation and purification of the solid supports, but they were also measured directly in the reaction vessels. Even the detection of Raman‐active functional groups in swollen polymer resins and in reaction mixtures was demonstrated, and allows real‐time observation of the progress of diverse reactions on solid supports.
Solid distribution and mixing time in stirred tanks: The case of floating particles
Authors: Paglianti Alessandro , Carletti Claudio , Busciglio Antonio , Montante Giuseppina
Published: April 2017

This work concerns floating particle distribution and liquid mixing dynamics in a solid‐liquid stirred tank. Measurements of local solids concentration distribution at steady‐state conditions and of liquid homogenization in the presence of dispersed particles at transient conditions are collected with up‐pumping and down‐pumping pitched blade turbines. Electrical resistance tomography is the selected experimental technique for the data acquisition in the opaque solid‐liquid mixture. For the time dependent conductivity data processing, the same method commonly applied to the mixing time determination from planar laser induced fluorescence measurements is considered. The method is successfully extended to the characterization of liquid mixing with floating particles. The local data obtained by the ERT technique over the whole vessel volume are fully exploited. The robustness of the method for tackling conductivity variations close to the liquid free surface and due to the particles movement is assessed.
Two‐step principal component analysis for dynamic processes monitoring
Authors: Lou Zhijiang , Shen Dong , Wang Youqing
Published: April 2017

In this study, a two‐step principal component analysis (TS‐PCA) is proposed to handle the dynamic characteristics of chemical industrial processes in both steady state and unsteady state. Differently from the traditional dynamic PCA (DPCA) dealing with the static cross‐correlation structure and dynamic auto‐correlation structure in process data simultaneously, TS‐PCA handles them in two steps: it first identifies the dynamic structure by using the least squares algorithm, and then monitors the innovation component by using PCA. The innovation component is time uncorrelated and independent of the initial state of the process. As a result, TS‐PCA can monitor the process in both steady state and unsteady state, whereas all other reported dynamic approaches are limited to only processes in steady state. Even tested in steady state, TS‐PCA still can achieve better performance than the existing dynamic approaches.
Effect of the Functionalization Process on the Colloidal, Magnetic Resonance Imaging, and Bioelimination Properties of Mono‐ or Bisphosphonate‐Anchored Dendronized Iron Oxide Nanoparticles
Authors: Walter Aurélie , Garofalo Antonio , Bonazza Pauline , Meyer Florent , Martinez Hervé , Fleutot Solenne , Billotey Claire , Taleb Jacqueline , Felder‐Flesch Delphine , Begin‐Colin Sylvie
Published: April 2017

The functionalization process of iron oxide nanoparticles (NPs) is a major step and has to ensure a small particle size distribution (below 100 nm) and to preserve good magnetic properties suitable for in vivo applications. Two functionalization processes are here compared to coat iron oxide NPs, synthesized by thermal decomposition, with dendron molecules bearing either a mono‐ or a bisphosphonate anchoring group. The two processes are direct ligand exchange and the simultaneous ligand exchange and phase transfer process. The latter process led to a larger size distribution than the former. The phosphonate group is confirmed to be a strong anchoring agent from X‐ray photoelectron spectroscopy (XPS) and IR characterizations whatever the grafting process and the number of phosphonate groups, it also confirms the preservation of the NPs’ magnetic properties. All dendronized NPs display good in vitro MRI properties and those obtained by direct exchange showed no cell internalization, an efficient in vivo MRI contrast enhancement, and elimination by both urinary and hepato‐biliary ways.
The evolution of the major histocompatibility complex in upstream versus downstream river populations of the longnose dace
Authors: Crispo Erika , Tunna Haley R. , Hussain Noreen , Rodriguez Silvia S. , Pavey Scott A. , Jackson Leland J. , Rogers Sean M.
Published: April 2017

Populations in upstream versus downstream river locations can be exposed to vastly different environmental and ecological conditions and can thus harbor different genetic resources due to selection and neutral processes. An interesting question is how upstream–downstream directionality in rivers affects the evolution of immune response genes. We used next‐generation amplicon sequencing to identify eight alleles of the major histocompatibility complex (MHC) class II β exon 2 in the cyprinid longnose dace (Rhinichthys cataractae) from three rivers in Alberta, upstream and downstream of municipal and agricultural areas along contaminant gradients. We used these data to test for directional and balancing selection on the MHC. We also genotyped microsatellite loci to examine neutral population processes in this system. We found evidence for balancing selection on the MHC in the form of increased nonsynonymous variation relative to neutral expectations, and selection occurred at more amino acid residues upstream than downstream in two rivers. We found this pattern despite no population structure or isolation by distance, based on microsatellite data, at these sites. Overall, our results suggest that MHC evolution is driven by upstream–downstream directionality in fish inhabiting this system.
Design of the effect of adaptive servo‐ventilation on survival and cardiovascular hospital admissions in patients with heart failure and sleep apnoea: the ADVENT‐HF trial
Authors: Lyons Owen D. , Floras John S. , Logan Alexander G. , Beanlands Robert , Cantolla Joaquin Durán , Fitzpatrick Michael , Fleetham John , John Kimoff R. , Leung Richard S.T. , Lorenzi Filho Geraldo , Mayer Pierre , Mielniczuk Lisa , Morrison Debra L. , Ryan Clodagh M. , Series Frederic , Tomlinson George A. , Woo Anna , Arzt Michael , Parthasarathy Sairam , Redolfi Stefania , Kasai Takatoshi , Parati Gianfranco , Delgado Diego H. , Bradley T. Douglas ,   for the ADVENT‐HF Investigators
Published: April 2017

Introduction

Both types of sleep‐disordered breathing (SDB), obstructive and central sleep apnoea (OSA and CSA, respectively), are common in patients with heart failure and reduced ejection fraction (HFrEF). In such patients, SDB is associated with increased cardiovascular morbidity and mortality but it remains uncertain whether treating SDB by adaptive servo‐ventilation (ASV) in such patients reduces morbidity and mortality.

Aim

ADVENT‐HF is designed to assess the effects of treating SDB with ASV on morbidity and mortality in patients with HFrEF.

Methods

ADVENT‐HF is a multicentre, multinational, randomized, parallel‐group, open‐label trial with blinded assessment of endpoints of standard medical therapy for HFrEF alone vs. with the addition of ASV in patients with HFrEF and SDB. Patients with a history of HFrEF undergo echocardiography and polysomnography. Those with a left ventricular ejection fraction ≤45% and SDB (apnoea–hypopnoea index ≥15) are eligible. SDB is stratified into OSA with ≥50% of events obstructive or CSA with >50% of events central. Those with OSA must not have excessive daytime sleepiness (Epworth score of ≤10). Patients are then randomized to receive or not receive ASV. The primary outcome is the composite of all‐cause mortality, cardiovascular hospital admissions, new‐onset atrial fibrillation requiring anti‐coagulation but not hospitalization, and delivery of an appropriate discharge from an implantable cardioverter‐defibrillator not resulting in hospitalization during a maximum follow‐up time of 5 years.

Conclusion

The ADVENT‐HF trial will help to determine whether treating SDB by ASV in patients with HFrEF improves morbidity and mortality.
Synthesis and characterization of a new biobased poly(urethane‐ester) from ricinoleic acid and its use as biopolymeric matrix for magnetic nanocomposites
Authors: Péres Eduardo Ulisses Xavier , Sousa Marcelo Henrique , Gomes de Souza Fernando , Machado Fabricio , Suarez Paulo Anselmo Ziani
Published: April 2017

This work presents a new biobased poly(urethane‐ester) synthesized from ricinoleic acid (RA), 1,6‐diisocyanatehexane, and glycerol through bulk polymerization. RA‐modified magnetic iron oxide nanoparticles, previously obtained through coprecipitation technique, were introduced in situ to produce a magnetic nanocomposite. DSC analyses revealed that the glass transition (Tg) of the biobased poly(urethane‐ester) was equal to −75°C, and for the magnetic biobased poly(urethane‐ester) the Tg was reduced in approximately 3°C. DTG analyses were used to measure the thermal stability and the amount of magnetic nanoparticle dispersed into the polymeric matrix, indicating that the polymeric materials exhibit good thermal stability and the fraction of nanoparticles dispersed into the biobased poly(urethane‐ester) matrix was equal to 2.19 wt%. Infrared spectroscopy and NMR were used to recognize functional groups in structures and follow the reaction evolution. Magnetic force, hysteresis loops and XRD essays used to provide magnetic features of the materials, showed that crystallite size of the mono domains was equal to 7.6 nm and that magnetic materials exhibit superparamagnetic behavior. GPC was used to evaluate average molar mass of polymer, determined equal to 2569 Da and molar mass dispersity equal to 2.4.

Practical applications: Introducing magnetic nanoparticles into polymeric matrix leads to composites with unique properties, allowing different applications. Besides, the use of vegetable oils to produce polymer has many advantages such as biocompatibility and renewability. Due to their physico‐chemical and biocompatibility properties the magnetic nanocomposites using castor bean oil prepared in the present work may have potential candidates for several applications, like biomedical implants, tissue engineering, and controlled drug delivery.

This article describes the preparation of a new biobased poly(urethane‐ester) synthesized from ricinoleic acid (RA), 1,6‐diisocyanatehexane, and glycerol and its use as polymeric matrix in magnetic nanocomposite. The polymer is characterized by FTIR, 1H NMR, TG, and DSC. The composite is studied by magnetic force exhibiting superparamagnetic behavior.
About water degumming and the hydration of non‐hydratable phosphatides
Authors: Dijkstra Albert J.
Published: April 2017

Although we have been degumming and neutralizing oils for over a century, we still do not know the mechanisms of these reactions in detail. The present “Hypothesis Paper” reviews a number of outstanding questions, raises a number of further questions but also provides some answers. The main outstanding question concerns the hydration of phosphatides during water degumming: is this thermodynamically or kinetically controlled? Crucial experiments show it to be controlled by the thermodynamically determined partition coefficients. One of the further questions concerns the compounds present in oil that contain phosphorus but differ from the known phosphatides. One of the suggested answers concerns the “charge balance” of the water degumming process. By assuming that the phosphatidic acid that is removed during water degumming is removed as its potassium salt and that the calcium that is removed is removed as calcium soap, the positive and negative charges involved in the water degumming process can be made to balance. The paper also confirms that complete removal of phosphatides requires a really strong and concentrated base

Practical applications: Almost all oil produced worldwide is either degummed or neutralized or both. Gaining insight in the chemistry involved must surely lead to practical applications and savings which, given the scale of operation, will be quite substantial.

Crude oil contains various phosphatides that are removed during the degumming and the refining processes. It has now been found that this removal is thermodynamically controlled rather than kinetically as reported in the literature. The removal of non‐hydratable phosphatides on prolonged exposure to water has been found to be by autocatalytic hydrolysis. It has also been found that by assuming that the calcium that is removed during water degumming leaves the oil as calcium soaps, the positive and negative molecules that disappear on degumming are in balance. Even so, the question by what mechanism the non‐hydratable phosphatides are removed during alkali refining still has to be resolved.
Dendrogeomorphic chronologies of landslides: Dating of true slide movements?
Authors: Šilhán Karel
Published: April 2017

Dendrogeomorphic chronologies of landslide movements are frequently used to investigate past landslide activity. Slide areas are often affected by other slope movements (e.g. creep) simultaneously. Trees growing on landslides record all types of ground movements, which potentially creates significant noise in tree ring based chronologies of landslide movements. The effect of creep movements on dendrogeomorphic landslide chronologies was evaluated in a block‐type landslide in the south‐western foreland of the Orlické hory Mountains. In total, 272 trees (Picea abies and Fagus sylvatica) were sampled (1088 increment cores) on the sub‐horizontal surfaces of rotated slide blocks, which were presumably created only by slide movements, and on the steep internal scarps separating landslide blocks, which were presumably created and affected by a combination of slide and creep movements. Ground movements were dated based on growth disturbances identified in an analysis of eccentric tree growth.

The trees growing on the internal landslide scarps separating the rotated blocks exhibited a significantly higher number and frequency of growth disturbances than those growing on the sub‐horizontal block surfaces. All eight dated block surface movements were also identified on the internal scarps. Creep‐based events represented as many as 70% of the dated movement events on the internal scarps. Varying the It thresholds did not filter out more than 40% of the noise without significantly reducing the number of true dated slide events. A significant difference was observed between the ability of P. abies and F. sylvatica to record ground movements by eccentric growth. Probably due to its shallower roots (and weaker anchoring of the tree to landslide blocks), P. abies appears to be more sensitive to surficial ground movement, which potentially increases the proportion of dated creep events (noise). Thus, the careful selection of sampled tree species with different physiologies should be considered during dendrogeomorphic field sampling. Copyright © 2017 John Wiley & Sons, Ltd.
Moving immersed boundary method
Authors: Cai Shang‐Gui , Ouahsine Abdellatif , Favier Julien , Hoarau Yannick
Published: April 2017

A novel implicit immersed boundary method of high accuracy and efficiency is presented for the simulation of incompressible viscous flow over complex stationary or moving solid boundaries. A boundary force is often introduced in many immersed boundary methods to mimic the presence of solid boundary, such that the overall simulation can be performed on a simple Cartesian grid. The current method inherits this idea and considers the boundary force as a Lagrange multiplier to enforce the no‐slip constraint at the solid boundary, instead of applying constitutional relations for rigid bodies. Hence excessive constraint on the time step is circumvented, and the time step only depends on the discretization of fluid Navier‐Stokes equations, like the CFL condition in present work. To determine the boundary force, an additional moving force equation is derived. The dimension of this derived system is proportional to the number of Lagrangian points describing the solid boundaries, which makes the method very suitable for moving boundary problems since the time for matrix update and system solving is not significant. The force coefficient matrix is made symmetric and positive definite so that the conjugate gradient method can solve the system quickly. The proposed immersed boundary method is incorporated into the fluid solver with a second‐order accurate projection method as a plug‐in. The overall scheme is handled under an efficient fractional step framework, namely, prediction, forcing, and projection. Various simulations are performed to validate current method, and the results compare well with previous experimental and numerical studies.
A dissipation‐free numerical method to solve one‐dimensional hyperbolic flow equations
Authors: Cao Zhiwei , Liu Zhifeng , Wang Xiaohong , Shi Anfeng , Luo Haishan , Noetinger Benoît
Published: April 2017

In this paper, a numerical method to capture the shock wave propagation in 1‐dimensional fluid flow problems with 0 numerical dissipation is presented. Instead of using a traditional discrete grid, the new numerical method is built on a range‐discrete grid, which is obtained by a direct subdivision of values around the shock area. The range discrete grid consists of 2 types: continuous points and shock points. Numerical solution is achieved by tracking characteristics and shocks for the movements of continuous and shock points, respectively. Shocks can be generated or eliminated when triggering entropy conditions in a marking step. The method is conservative and total variation diminishing. We apply this new method to several examples, including solving Burgers equation for aerodynamics, Buckley‐Leverett equation for fractional flow in porous media, and the classical traffic flow. The solutions were verified against analytical solutions under simple conditions. Comparisons with several other traditional methods showed that the new method achieves a higher accuracy in capturing the shock while using much less grid number. The new method can serve as a fast tool to assess the shock wave propagation in various flow problems with good accuracy.
Crosstalk of LKB1‐regulated and PTEN‐regulated signals in liver morphogenesis and tumor development in mice
Authors: Jia Chengyou , Medina Vivian , Liu Chenchang , He Lina , Qian Daohai , Tu Taojian , Okamoto Curtis T. , Stiles Bangyan L.
Published: April 2017

Liver kinase B 1 (LKB1 or STK11) and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) are two tumor suppressors that regulate the mammalian target of rapamycin signaling pathway. Deletion studies show that loss of either Lkb1 (Lkb+/–
) or Pten (PtenloxP/loxP; Alb‐Cre+
) leads to liver injury and development of hepatocarcinoma. In this study, we investigated the crosstalk of LKB1 and PTEN loss during tumorigenesis and liver development. We show that haplo‐insufficiency of Lkb1 in the liver leads to advanced tumor development in Pten‐null mice (PtenloxP/loxP; LkbloxP/+; Alb‐Cre+
). Our analysis shows that LKB1 and PTEN interact with each other in their regulation of fatty acid synthase as well as p21 expression. The combined loss of LKB1 and PTEN (PtenloxP/loxP; LkbloxP/loxP; Alb‐Cre+
) also leads to the inability to form zonal structures in the liver. The lack of metabolic zonal structures is consistent with the inability of the livers to store glycogen as well as elevated plasma bilirubin and alanine aminotransferase, indicative of liver dysfunction. These structural and functional defects are associated with cytoplasm distribution of a canalicular membrane protein multidrug resistant protein 2, which is responsible for clearing bilirubin. This observed regulation of multidrug resistant protein 2 by LKB1 likely contributes to the lack of cellular polarity and the early lethality phenotype associated with the homozygous loss of Lkb1 alone or in combination with Pten. Finally, Pten deletion does not rescue the precocious ductal plate formation reported for Lkb1‐deleted livers. Conclusion: Our study dissected the functional and molecular crosstalk of PTEN and LKB1 and elucidated key molecular targets for such interactions. (Hepatology Communications 2017;1:153‐167)
Evaluating the hydrological and hydrochemical responses of a High Arctic catchment during an exceptionally warm summer
Authors: Lamhonwah Daniel , Lafrenière Melissa J. , Lamoureux Scott F. , Wolfe Brent B.
Published: April 2017

The Arctic has experienced substantial warming during the past century with models projecting continued warming accompanied by increases in summer precipitation for most regions. A key impact of increasing air surface temperatures is the deepening of the active layer, which is expected to alter hydrological processes and pathways. The aim of this study was to determine how one of the warmest and wettest summers in the past decade at a High Arctic watershed impacted water infiltration and storage in deeply thawed soil and solute concentrations in stream runoff during the thaw period. In June and July 2012 at the Cape Bounty Watershed Observatory, we combined active layer measurements with major ion concentrations and stable isotopes in surface waters to characterize the movement of different runoff sources: snowmelt, rainfall, and soil water. Results indicate that deep ground thaw enhanced the storage of infiltrated water following rainfall. Soil water from infiltrated rainfall flowed through the thawed transient layer and upper permafrost, which likely solubilized ions previously stored at depth. Subsequent rainfall events acted as a hydrological flushing mechanism, mobilizing solutes from the subsurface to the surface. This solute flushing substantially increased ion concentrations in stream runoff throughout mid to late July. Results further suggest the importance of rainfall and soil water as sources of runoff in a High Arctic catchment during mid to late summer as infiltrated snowmelt is drained from soil following baseflow. Although there was some evaporation of surface water, our study indicates that flushing from solute stores in the transient layer was the primary driver of increased ion concentrations in stream runoff and not evaporative concentration of surface water. With warmer and wetter summers projected for the Arctic, ion concentrations in runoff (especially in the late thaw season), will likely increase due to the deep storage and subsurface flow of infiltrated water and subsequent flushing of previously frozen solutes to the surface.
The proprotein convertase furin in tumour progression
Authors: Jaaks Patricia , Bernasconi Michele
Published: April 2017

Proprotein convertases are proteases that have been implicated in the activation of a wide variety of proteins. These proteins are generally synthesised as precursor proteins and require limited proteolysis for conversion into their mature bioactive counterparts. Many of these proteins, including metalloproteases, growth factors and their receptors or adhesion molecules, have been shown to facilitate tumour formation and progression. Hence, this review will focus on the proprotein convertase furin and its role in cancer. The expression of furin has been confirmed in a large spectrum of cancers such as head and neck squamous cell carcinoma, breast cancer and rhabdomyosarcoma. Functional studies modulating furin activity uncovered its importance for the processing of many cancer‐related substrates and strongly indicate that high furin activity promotes the malignant phenotype of cancer cells. In this review, we summarise the expression and function of furin in different cancer types, discuss its role in processing cancer‐related proproteins and give examples of potential therapeutic approaches that take advantage of the proteolytic activity of furin in cancer cells.
Single nucleotide polymorphisms in the IGF‐IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE‐3 trial
Authors: Schirripa Marta , Zhang Wu , Heinemann Volker , Cao Shu , Okazaki Satoshi , Yang Dongyun , Loupakis Fotios , Berger Martin D. , Ning Yan , Miyamoto Yuji , Suenaga Mitsukuni , Gopez Roel F. , West Jordan D. , Hanna Diana , Barzi Afsaneh , Falcone Alfredo , Stintzing Sebastian , Lenz Heinz‐Josef
Published: April 2017

The Insulin‐like growth factor (IGF)/IGF‐receptor pathway with its scaffolding proteins Insulin Receptor Substrate (IRS)1 and IRS2 are crucial regulators of metabolism and progression in metastatic colorectal cancer (mCRC). The goal of the study was the identification of predictive and prognostic markers among IRS1, IRS2, IGF1 and IGF‐1R SNPs in mCRC patients enrolled in the FIRE‐3 trial. Four SNPs of IRS (IRS1 rs1801278, rs1801123; IRS2 rs1805097, rs2289046) and four SNPs of IGF1‐IGFR1 (rs6214, rs6220, rs2946834, rs2016347) were analyzed by PCR/direct‐sequencing in the FIRE‐3 trial. The relation of SNPs with PFS and OS was evaluated through Kaplan–Meier method and log‐rank test in the overall population and in subgroup according to RAS status and treatment arm. In the overall population IRS1 rs1801123 C/‐ carriers (N= 105) achieved significantly worse OS compared to T/T (N = 464) in univariate (HR = 1.32 [95%CI 1.03‐1.70], p = 0.029) and in multivariable. Similar results were observed among RAS wild type. Patients with IGF1 rs2946834 T/‐ variant (N= 280) achieved improved PFS compared to C/C (N = 257) in univariate (HR = 0.77 [95%CI 0.64‐0.92], p = 0.004) and in multivariable. In the RAS wild‐type subgroup IGF1 rs2946834 T/‐ carriers showed better PFS and OS compared to C/C (univariate HR for PFS = 0.65 [95%CI 0.51–0.81], p < 0.001; multivariable HR for PFS = 0.63 [95%CI 0.50–0.81], p < 0.001). IRS1 rs1801123 SNP was identified as a new prognostic marker for mCRC. IGF1 rs2946834 was confirmed as prognostic factor in the overall population and in RAS wild type patients. Our findings underline the importance of IGF downstream signaling pathway in RAS wild‐type mCRC patient.
Worldwide burden of cancer attributable to HPV by site, country and HPV type
Authors: de Martel Catherine , Plummer Martyn , Vignat Jerome , Franceschi Silvia
Published: April 2017

HPV is the cause of almost all cervical cancer and is responsible for a substantial fraction of other anogenital cancers and oropharyngeal cancers. Understanding the HPV‐attributable cancer burden can boost programs of HPV vaccination and HPV‐based cervical screening. Attributable fractions (AFs) and the relative contributions of different HPV types were derived from published studies reporting on the prevalence of transforming HPV infection in cancer tissue. Maps of age‐standardized incidence rates of HPV‐attributable cancers by country from GLOBOCAN 2012 data are shown separately for the cervix, other anogenital tract and head and neck cancers. The relative contribution of HPV16/18 and HPV6/11/16/18/31/33/45/52/58 was also estimated. 4.5% of all cancers worldwide (630,000 new cancer cases per year) are attributable to HPV: 8.6% in women and 0.8% in men. AF in women ranges from <3% in Australia/New Zealand and the USA to >20% in India and sub‐Saharan Africa. Cervix accounts for 83% of HPV‐attributable cancer, two‐thirds of which occur in less developed countries. Other HPV‐attributable anogenital cancer includes 8,500 vulva; 12,000 vagina; 35,000 anus (half occurring in men) and 13,000 penis. In the head and neck, HPV‐attributable cancers represent 38,000 cases of which 21,000 are oropharyngeal cancers occurring in more developed countries. The relative contributions of HPV16/18 and HPV6/11/16/18/31/33/45/52/58 are 73% and 90%, respectively. Universal access to vaccination is the key to avoiding most cases of HPV‐attributable cancer. The preponderant burden of HPV16/18 and the possibility of cross‐protection emphasize the importance of the introduction of more affordable vaccines in less developed countries.
Pre‐ and post‐diagnostic beta‐blocker use and prognosis after colorectal cancer: Results from a population‐based study
Authors: Jansen Lina , Weberpals Janick , Kuiper Josephina G. , Vissers Pauline A.J. , Wolkewitz Martin , Hoffmeister Michael , Brenner Hermann
Published: April 2017

Recent experimental and epidemiological studies have suggested that beta‐blocker use might be associated with better cancer prognosis, but results were inconclusive and only few studies have investigated the association specifically for colorectal cancer (CRC) patients. We investigated this hypothesis using a linked dataset of the Eindhoven area of the Netherlands Cancer Registry and the PHARMO record linkage, including patients diagnosed with CRC between 1998 and 2011. Eligible patients were matched on propensity scores to control for potential confounders such as socio‐demographic factors, comorbidity, cancer treatment and use of other medications. Controls were subsequently restricted to active comparators. The association between pre‐diagnostic and time‐dependent post‐diagnostic beta‐blocker use and overall survival was estimated using Cox proportional hazard regression models. Subgroup analyses by cancer site and stage and by beta‐blocker type were conducted. Of 8,100 CRC patients with a median follow‐up of 6.6 years, 1,813 (22%) used beta‐blockers prior to diagnosis. In multivariate analysis, we observed no significant association in overall mortality for pre‐diagnostic [hazard ratio 1.07, 95% confidence interval (0.96‐1.19)] and post‐diagnostic [1.10 (0.98‐1.23)] beta‐blocker use, respectively. Analyses by beta‐blocker type, by cancer site, cancer stage and by cumulative dose showed no significant survival improvements for beta‐blocker users. However, there was a significant association between cumulative duration of use of 1‐12 months and increased overall mortality [1.20 (1.03‐1.39)]. Thus, our results do not support the hypothesis of a beneficial effect of pre‐ or post‐diagnostic beta‐blocker intake on CRC prognosis, neither for specific patient subgroups nor for specific types of beta‐blockers.
Quantum chemical calculations of tryptophan → heme electron and excitation energy transfer rates in myoglobin
Authors: Suess Christian J. , Hirst Jonathan D. , Besley Nicholas A.
Published: April 2017

The development of optical multidimensional spectroscopic techniques has opened up new possibilities for the study of biological processes. Recently, ultrafast two‐dimensional ultraviolet spectroscopy experiments have determined the rates of tryptophan → heme electron transfer and excitation energy transfer for the two tryptophan residues in myoglobin (Consani et al., Science, 2013, 339, 1586). Here, we show that accurate prediction of these rates can be achieved using Marcus theory in conjunction with time‐dependent density functional theory. Key intermediate residues between the donor and acceptor are identified, and in particular the residues Val68 and Ile75 play a critical role in calculations of the electron coupling matrix elements. Our calculations demonstrate how small changes in structure can have a large effect on the rates, and show that the different rates of electron transfer are dictated by the distance between the heme and tryptophan residues, while for excitation energy transfer the orientation of the tryptophan residues relative to the heme is important. © 2017 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.
Impact of shared care program in follow‐up of childhood cancer survivors: An intervention study
Authors: Ducassou Stéphane , Chipi Maïté , Pouyade Aurélie , Afonso Mélanie , Demeaux Jean‐Louis , Ducos Gérard , Pérel Yves , Ansoborlo Sophie
Published: April 2017

Background

With the growing rate of childhood cancer cure and the risks of sequelae, long‐term follow‐up (FU) of survivors is a central issue. Several models have been proven far from satisfactory. Shared care FU is the result of collaboration between general practitioners (GPs) and cancer centers. We sought to demonstrate the feasibility of setting up a shared care program based on the patient‐centered education of GPs and to evaluate the impact of this model in an intervention study.

Methods

We compared the FU care achievement in two childhood cancer survivor cohorts in the same pediatric oncology center, (i) control group (n = 134) and (ii) intervention study cohort (n = 137), after setting up the program.

Results

The rate of survivors answering the survey and the rate of patients involved in FU by their GPs were higher in intervention study cohort than in baseline one (132/137 vs. 72/134 and 110/132 vs. 13/72; P ≤ 0.0001). The lack of any FU was definitely lower (10/132 vs. 18/72; P = 0.001) in the intervention study cohort.

Conclusion

In this shared care program, survivors overcame distrust in their GP's knowledge and entered the FU program after their GPs had been involved in patient‐centered education. Personalized and incentive‐based guidance was very useful in helping survivors to adhere to FU. Support of a dedicated long‐term FU team was very useful. A nationwide organization, consideration of special needs in subgroups of survivors and sustained funding are needed to adjust the program in the very long term.
Effectiveness of a pragmatic school‐based universal intervention targeting student resilience protective factors in reducing mental health problems in adolescents
Authors: Dray Julia , Bowman Jenny , Campbell Elizabeth , Freund Megan , Hodder Rebecca , Wolfenden Luke , Richards Jody , Leane Catherine , Green Sue , Lecathelinais Christophe , Oldmeadow Christopher , Attia John , Gillham Karen , Wiggers John
Published: April 2017

Worldwide, 10–20% of adolescents experience mental health problems. Strategies aimed at strengthening resilience protective factors provide a potential approach for reducing mental health problems in adolescents. This study evaluated the effectiveness of a universal, school‐based intervention targeting resilience protective factors in reducing mental health problems in adolescents. A cluster randomised controlled trial was conducted in 20 intervention and 12 control secondary schools located in socio‐economically disadvantaged areas of NSW, Australia. Data were collected from 3115 students at baseline (Grade 7, 2011), of whom 2149 provided data at follow up (Grade 10, 2014; enrolments in Grades 7 to 10 typically aged 12–16 years; 50% male; 69.0% retention). There were no significant differences between groups at follow‐up for three mental health outcomes: total SDQ, internalising problems, and prosocial behaviour. A small statistically significant difference in favour of the control group was found for externalising problems. Findings highlight the continued difficulties in developing effective, school‐based prevention programs for mental health problems in adolescents.

Trial registration

ANZCTR (Ref no: ACTRN12611000606987).
Effect of long‐term storage in biobanks on cerebrospinal fluid biomarker Aβ1‐42, T‐tau, and P‐tau values
Authors: Willemse Eline A.J. , van Uffelen Kees W.J. , van der Flier Wiesje M. , Teunissen Charlotte E.
Published: April 2017

Introduction

We studied the effect of long‐term storage at −80°C on cerebrospinal fluid (CSF) biomarker levels. Our approach assumed consistency of mean biomarker levels in a homogenous Alzheimer's disease patient cohort over time.

Methods

We selected 148 Alzheimer's disease samples that had inclusion dates equally distributed over the years 2001 to 2013 from our biobank. The concentrations of CSF biomarkers, amyloid β1–42 (Aβ1–42), total tau (T‐tau), and phosphorylated tau181 (P‐tau), were measured with one enzyme‐linked immunosorbent assay lot. Results were compared with historical results obtained at biobank inclusion.

Results

Linear regression analyses showed that the levels of CSF biomarkers, Aβ1–42, T‐tau, and P‐tau, were not related to storage time at −80°C (β = 0.015, 0.048, and 0.0016 pg/mL per day, not significant). However, the differences between remeasured concentrations of Aβ1–42 and concentrations at biobank inclusion measured for more than 30 assay batches increased with increasing time difference.

Discussion

The levels of CSF biomarkers, Aβ1–42, T‐tau, and P‐tau, did not significantly change during the maximum period of 12 years of storage at −80°C. Batch variation for Aβ1–42 is a factor that should be controlled for when using historical cohorts.
eTumorType, An Algorithm of Discriminating Cancer Types for Circulating Tumor Cells or Cell-Free DNAs in Blood
Authors: Zou Jinfeng , Wang Edwin
Published: April 2017

With the technology development on detecting circulating tumor cells (CTCs) and cell-free DNAs (cfDNAs) in blood, serum, and plasma, non-invasive diagnosis of cancer becomes promising. A few studies reported good correlations between signals from tumor tissues and CTCs or cfDNAs, making it possible to detect cancers using CTCs and cfDNAs. However, the detection cannot tell which cancer types the person has. To meet these challenges, we developed an algorithm, eTumorType, to identify cancer types based on copy number variations (CNVs) of the cancer founding clone. eTumorType integrates cancer hallmark concepts and a few computational techniques such as stochastic gradient boosting, voting, centroid, and leading patterns. eTumorType has been trained and validated on a large dataset including 18 common cancer types and 5327 tumor samples. eTumorType produced high accuracies (0.86–0.96) and high recall rates (0.79–0.92) for predicting colon, brain, prostate, and kidney cancers. In addition, relatively high accuracies (0.78–0.92) and recall rates (0.58–0.95) have also been achieved for predicting ovarian, breast luminal, lung, endometrial, stomach, head and neck, leukemia, and skin cancers. These results suggest that eTumorType could be used for non-invasive diagnosis to determine cancer types based on CNVs of CTCs and cfDNAs.