bluuebunny/crossref_metadata_2025 huggingface dataset:
Inequality in active ageing: evidence from a new individual-level index for European countries
Authors: BARSLUND MIKKEL , VON WERDER MARTEN , ZAIDI ASGHAR
Published: October 2017

In the context of emerging challenges and opportunities associated with population ageing, the study of inequality in active-ageing outcomes is critical to the design of appropriate and effective social policies. While there is much discussion about active ageing at the aggregate country level, little is known about inequality in active-ageing experiences within countries. Based on the existing literature on active ageing, this paper proposes an individual-level composite active ageing index based on Survey of Health, Ageing and Retirement in Europe (SHARE) data. The individual-level nature of the index allows us to analyse inequality in experiences of active ageing within selected European countries. One important motivation behind measuring active ageing at the individual level is that it allows for a better understanding of unequal experiences of ageing, which may otherwise be masked in aggregate-level measures of active ageing. Results show large differences in the distribution of individual-level active ageing across the 13 European countries covered and across age groups. Furthermore, there is a positive association between the country-level active ageing index and the equality of its distribution within a country. Hence, countries with the lowest average active ageing index tend to have the most unequal distribution in active-ageing experiences. For nine European countries, where temporal data are also available, we find that inequality in active-ageing outcomes decreased in the period 2004 to 2013.
Obstacle Avoidance Approaches for Autonomous Navigation of Unmanned Surface Vehicles
Authors: Polvara Riccardo , Sharma Sanjay , Wan Jian , Manning Andrew , Sutton Robert
Published: October 2017

The adoption of a robust collision avoidance module is required to realise fully autonomous Unmanned Surface Vehicles (USVs). In this work, collision detection and path planning methods for USVs are presented. Attention is focused on the difference between local and global path planners, describing the most common techniques derived from classical graph search theory. In addition, a dedicated section is reserved for intelligent methods, such as artificial neural networks and evolutionary algorithms. Born as optimisation methods, they can learn a close-to-optimal solution without requiring large computation effort under certain constraints. Finally, the deficiencies of the existing methods are highlighted and discussed. It has been concluded that almost all the existing method do not address sea or weather conditions, or do not involve the dynamics of the vessel while defining the path. Therefore, this research area is still far from being considered fully explored.
Weight resilience and fruit and vegetable intake among African-American women in an obesogenic environment
Authors: Parisi Sara M , Bodnar Lisa M , Dubowitz Tamara
Published: October 2017

Objective

To investigate relationships between weight resilience (maintaining a normal weight in a food desert environment) and fruit and vegetable (F&V) intake, attitudes and barriers.

Design

Cross-sectional, in-person surveys collected May–December 2011, including self-reported data on F&V-related psychosocial factors, attitudes and barriers. Two 24 h dietary recalls were completed; weight and height were measured. Multivariable regression models estimated prevalence ratios (95 % CI).

Setting

Two low-income, predominantly African-American food deserts in Pittsburgh, Pennsylvania, USA.

Subjects

Women aged 18–49 years (n279) who were the primary food shopper in a household randomly selected for a parent study.

Results

Fifteen per cent were weight resilient, 30 % were overweight and 55 % were obese. Overall, 25 % reported eating ≥5 F&V servings/d. After adjustment for age, education, parity, employment, living alone, physical activity, per capita income and mean daily energy intake, women eating ≥5 F&V servings/d were 94 % more likely to be weight resilient compared with those eating <5 servings/d (1·94; 1·10, 3·43). Across BMI groups, self-efficacy regarding F&V consumption was high and few F&V barriers were reported. The most frequently reported barrier was concern about the cost of F&V (36 %). Of the attitudinal F&V-related factors, only concern about wasting food when serving F&V was associated with weight resilience in adjusted models (0·29; 0·09, 0·94). In a model predicting consuming ≥5 F&V servings/d, driving one’s own car to the store was the only attitudinal F&V-related factor associated with consumption (1·50; 1·00, 2·24).

Conclusions

In this population, weight resilience may be encouraged by improving access to affordable and convenient F&V options and providing education on ways to make them palatable to the entire household, rather than by shifting women’s F&V perceptions, which are already positive.
A qualitative study conducted in the USA exploring Latino fathers’ beliefs, attitudes and practices related to their young children’s eating, physical activity and sedentary behaviours
Authors: Lindsay Ana Cristina , Wallington Sherrie F , Muñoz Mario A , Greaney Mary L
Published: October 2017

Objective

Increasing evidence documents fathers’ influential role in their children’s eating, physical activity (PA) and sedentary behaviours (SB). We aimed to expand limited existing research examining fathers’ influence in these areas by exploring Latino fathers’ beliefs, attitudes and practices related to eating, PA and SB of their young children.

Design

Seven focus group discussions were conducted in Spanish with Latino fathers (n 28) of children aged 2–8 years. Audio recordings were transcribed and translated verbatim without identifiers. Data were analysed using thematic analysis to identify key concepts and themes using NVivo 11 software.

Results

Fathers expressed positive beliefs and attitudes about the importance of healthy eating for their young children, themselves and their families. Nevertheless, the majority reported familial practices including eating out, getting take-out, etc. that have been linked to increased obesity risk among Latino children. Fathers were more involved and engaged in children’s PA than eating and feeding. However, several fathers reported engaging predominantly in sedentary activities with their children, appeared permissive of children’s sedentary habits and struggled to set limits on children’s screen-time.

Conclusions

We provide new information on Latino fathers’ beliefs and child feeding and PA practices that may provide important targets for interventions aimed at promoting healthful eating and PA behaviours of Latino children. Future research should further quantify the influence of Latino fathers’ parenting styles and practices on development of children’s eating, PA and SB. This information is needed to identify risk factors amenable to interventions and to design culturally appropriate parenting and family-based interventions targeting Latino children’s home environment and designed to meet this ethnic group’s specific needs.
Early-Career Scientists Discuss Paleoscience, Future Challenges
Authors: Carter Vachel , Heinecke Liv , Maezumi S.
Published: October 2017

3rd PAGES Young Scientists Meeting; Morillo de Tou, Spain, 7–9 May 2017
Retinoic acid induces white adipose tissue browning by increasing adipose vascularity and inducing beige adipogenesis of PDGFRα+ adipose progenitors
Authors: Wang Bo , Fu Xing , Liang Xingwei , Deavila Jeanene M , Wang Zhixiu , Zhao Liang , Tian Qiyu , Zhao Junxing , Gomez Noe Alberto , Trombetta Sophie C , Zhu Mei-Jun , Du Min
Published: October 2017

Formation of beige adipocytes within white adipose tissue enhances energy expenditure, which is a promising strategy to reduce obesity and prevent metabolic symptoms. Vitamin A and its bioactive metabolite, retinoic acid (RA), have regulatory roles in lipid metabolism. Here we report that RA induces white adipose tissue browning via activating vascular endothelial growth factor (VEGF) signaling. RA triggered angiogenesis and elicited de novo generation of platelet-derived growth factor receptor α positive (PDGFRα+) adipose precursor cells via VEGFA/VEGFR2 signaling. In addition, RA promoted beige/brown adipocyte formation from capillary networks in vitro. Using PDGFRα tracking mice, we found that the vascular system acted as an adipogenic repository by containing PDGFRα+ progenitors which differentiated into beige adipocytes under RA or VEGF164 treatments. Conditional knockout of VEGF receptors blocked RA-stimulated white adipose tissue browning. Moreover, the VEGFA and RA activated p38MAPK to enhance the binding of RA receptor to RA response elements of the Prdm16 promoter and upregulated Prdm16 transcription. In conclusion, RA induces white adipose tissue browning by increasing adipose vascularity and promoting beige adipogenesis of PDGFRα+ adipose progenitors.
The impact of rare variation on gene expression across tissues
Authors:   GTEx Consortium, Li Xin , Kim Yungil , Tsang Emily K. , Davis Joe R. , Damani Farhan N. , Chiang Colby , Hess Gaelen T. , Zappala Zachary , Strober Benjamin J. , Scott Alexandra J. , Li Amy , Ganna Andrea , Bassik Michael C. , Merker Jason D. , Hall Ira M. , Battle Alexis , Montgomery Stephen B.
Published: October 2017

Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk1,2,3,4. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants1,5. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles1,6,7, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues8,9,10,11, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release12. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.
Advances in the physiological assessment and diagnosis of GERD
Authors:   on behalf of the International Working Group for Disorders of Gastrointestinal Motility and Function, Savarino Edoardo , Bredenoord Albert J. , Fox Mark , Pandolfino John E. , Roman Sabine , Gyawali C. Prakash
Published: October 2017

GERD is a common condition worldwide. Key mechanisms of disease include abnormal oesophagogastric junction structure and function, and impaired oesophageal clearance. A therapeutic trial of acid-suppressive PPI therapy is often the initial management, with endoscopy performed in the setting of alarm symptoms and to exclude other conditions. If symptoms persist and endoscopy does not reveal evidence of GERD, oesophageal function tests are performed, including oesophageal manometry and ambulatory reflux monitoring. However, reflux episodes can be physiological, and some findings on endoscopy and manometry can be encountered in asymptomatic individuals without GERD symptoms. The diagnosis of GERD on the basis of functional oesophageal testing has been previously reported, but no updated expert recommendations on indications and the interpretation of oesophageal function testing in GERD has been made since the Porto consensus over a decade ago. In this Consensus Statement, we aim to describe modern oesophageal physiological tests and their analysis with an emphasis on establishing indications and consensus on interpretation parameters of oesophageal function testing for the evaluation of GERD in clinical practice. This document reflects the collective conclusions of the international GERD working group, incorporating existing data with expert consensus opinion.
Anomalous Kondo resonance mediated by semiconducting graphene nanoribbons in a molecular heterostructure
Authors: Li Yang , Ngo Anh T. , DiLullo Andrew , Latt Kyaw Zin , Kersell Heath , Fisher Brandon , Zapol Peter , Ulloa Sergio E. , Hla Saw-Wai
Published: October 2017

Kondo resonances in heterostructures formed by magnetic molecules on a metal require free host electrons to interact with the molecular spin and create delicate many-body states. Unlike graphene, semiconducting graphene nanoribbons do not have free electrons due to their large bandgaps, and thus they should electronically decouple molecules from the metal substrate. Here, we observe unusually well-defined Kondo resonances in magnetic molecules separated from a gold surface by graphene nanoribbons in vertically stacked heterostructures. Surprisingly, the strengths of Kondo resonances for the molecules on graphene nanoribbons appear nearly identical to those directly adsorbed on the top, bridge and threefold hollow sites of Au(111). This unexpectedly strong spin-coupling effect is further confirmed by density functional calculations that reveal no spin–electron interactions at this molecule-gold substrate separation if the graphene nanoribbons are absent. Our findings suggest graphene nanoribbons mediate effective spin coupling, opening a way for potential applications in spintronics.
Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis
Authors: Lee Jong-Ho , Liu Rui , Li Jing , Zhang Chuanbao , Wang Yugang , Cai Qingsong , Qian Xu , Xia Yan , Zheng Yanhua , Piao Yuji , Chen Qianming , de Groot John F. , Jiang Tao , Lu Zhimin
Published: October 2017

Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis; however, its role and regulation in tumorigenesis are not well understood. Here, we demonstrate that PFK1 platelet isoform (PFKP) is the predominant PFK1 isoform in human glioblastoma cells and its expression correlates with total PFK activity. We show that PFKP is overexpressed in human glioblastoma specimens due to an increased stability, which is induced by AKT activation resulting from phosphatase and tensin homologue (PTEN) loss and EGFR-dependent PI3K activation. AKT binds to and phosphorylates PFKP at S386, and this phosphorylation inhibits the binding of TRIM21 E3 ligase to PFKP and the subsequent TRIM21-mediated polyubiquitylation and degradation of PFKP. PFKP S386 phosphorylation increases PFKP expression and promotes aerobic glycolysis, cell proliferation, and brain tumor growth. In addition, S386 phosphorylation in human glioblastoma specimens positively correlates with PFKP expression, AKT S473 phosphorylation, and poor prognosis. These findings underscore the potential role and regulation of PFKP in human glioblastoma development.
NCoR1 restrains thymic negative selection by repressing Bim expression to spare thymocytes undergoing positive selection
Authors: Wang Jianrong , He Nanhai , Zhang Na , Quan Dexian , Zhang Shuo , Zhang Caroline , Yu Ruth T. , Atkins Annette R. , Zhu Ruihong , Yang Chunhui , Cui Ying , Liddle Christopher , Downes Michael , Xiao Hui , Zheng Ye , Auwerx Johan , Evans Ronald M. , Leng Qibin
Published: October 2017

Thymocytes must pass both positive and negative selections to become mature T cells. Negative selection purges thymocytes whose T-cell receptors (TCR) exhibit high affinity to self-peptide MHC complexes (self pMHC) to avoid autoimmune diseases, while positive selection ensures the survival and maturation of thymocytes whose TCRs display intermediate affinity to self pMHCs for effective immunity, but whether transcriptional regulation helps conserve positively selected thymocytes from being purged by negative selection remains unclear. Here we show that the specific deletion of nuclear receptor co-repressor 1 (NCoR1) in T cells causes excessive negative selection to reduce mature thymocyte numbers. Mechanistically, NCoR1 protects positively selected thymocytes from negative selection by suppressing Bim expression. Our study demonstrates a critical function of NCoR1 in coordinated positive and negative selections in the thymus.
Regulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation
Authors: Xu Yiming , Wang Yong , Yan Siyuan , Yang Qiuhua , Zhou Yaqi , Zeng Xianqiu , Liu Zhiping , An Xiaofei , Toque Haroldo A. , Dong Zheng , Jiang Xuejun , Fulton David J. , Weintraub Neal L. , Li Qinkai , Bagi Zsolt , Hong Mei , Boison Detlev , Wu Chaodong , Huo Yuqing
Published: October 2017

The molecular mechanisms underlying vascular inflammation and associated inflammatory vascular diseases are not well defined. Here we show that endothelial intracellular adenosine and its key regulator adenosine kinase (ADK) play important roles in vascular inflammation. Pro-inflammatory stimuli lead to endothelial inflammation by increasing endothelial ADK expression, reducing the level of intracellular adenosine in endothelial cells, and activating the transmethylation pathway through increasing the association of ADK with S-adenosylhomocysteine (SAH) hydrolase (SAHH). Increasing intracellular adenosine by genetic ADK knockdown or exogenous adenosine reduces activation of the transmethylation pathway and attenuates the endothelial inflammatory response. In addition, loss of endothelial ADK in mice leads to reduced atherosclerosis and affords protection against ischemia/reperfusion injury of the cerebral cortex. Taken together, these results demonstrate that intracellular adenosine, which is controlled by the key molecular regulator ADK, influences endothelial inflammation and vascular inflammatory diseases.
Understanding activity and selectivity of metal-nitrogen-doped carbon catalysts for electrochemical reduction of CO2
Authors: Ju Wen , Bagger Alexander , Hao Guang-Ping , Varela Ana Sofia , Sinev Ilya , Bon Volodymyr , Roldan Cuenya Beatriz , Kaskel Stefan , Rossmeisl Jan , Strasser Peter
Published: October 2017

Direct electrochemical reduction of CO2 to fuels and chemicals using renewable electricity has attracted significant attention partly due to the fundamental challenges related to reactivity and selectivity, and partly due to its importance for industrial CO2-consuming gas diffusion cathodes. Here, we present advances in the understanding of trends in the CO2 to CO electrocatalysis of metal- and nitrogen-doped porous carbons containing catalytically active M–N
x
moieties (M = Mn, Fe, Co, Ni, Cu). We investigate their intrinsic catalytic reactivity, CO turnover frequencies, CO faradaic efficiencies and demonstrate that Fe–N–C and especially Ni–N–C catalysts rival Au- and Ag-based catalysts. We model the catalytically active M–N
x
moieties using density functional theory and correlate the theoretical binding energies with the experiments to give reactivity-selectivity descriptors. This gives an atomic-scale mechanistic understanding of potential-dependent CO and hydrocarbon selectivity from the M–N
x
moieties and it provides predictive guidelines for the rational design of selective carbon-based CO2 reduction catalysts.
A structural model of flagellar filament switching across multiple bacterial species
Authors: Wang Fengbin , Burrage Andrew M. , Postel Sandra , Clark Reece E. , Orlova Albina , Sundberg Eric J. , Kearns Daniel B. , Egelman Edward H.
Published: October 2017

The bacterial flagellar filament has long been studied to understand how a polymer composed of a single protein can switch between different supercoiled states with high cooperativity. Here we present near-atomic resolution cryo-EM structures for flagellar filaments from both Gram-positive Bacillus subtilis and Gram-negative Pseudomonas aeruginosa. Seven mutant flagellar filaments in B. subtilis and two in P. aeruginosa capture two different states of the filament. These reliable atomic models of both states reveal conserved molecular interactions in the interior of the filament among B. subtilis, P. aeruginosa and Salmonella enterica. Using the detailed information about the molecular interactions in two filament states, we successfully predict point mutations that shift the equilibrium between those two states. Further, we observe the dimerization of P. aeruginosa outer domains without any perturbation of the conserved interior of the filament. Our results give new insights into how the flagellin sequence has been “tuned” over evolution.
Observation of current-induced bulk magnetization in elemental tellurium
Authors: Furukawa Tetsuya , Shimokawa Yuri , Kobayashi Kaya , Itou Tetsuaki
Published: October 2017

The magnetoelectric effect in bulk matter is of growing interest both fundamentally and technologically. Since the beginning of the century, the magnetoelectric effect has been studied intensively in multiferroic materials. However, magnetoelectric phenomena in materials without any (anti-)ferroic order remain almost unexplored. Here we show the observation of a new class of bulk magnetoelectric effect, by revisiting elemental trigonal tellurium. We demonstrate that elemental tellurium, which is a nonmagnetic semiconductor, exhibits current-induced magnetization. This effect is attributed to spin splitting of the bulk band owing to the lack of inversion symmetry in trigonal tellurium. This finding highlights magnetoelectricity in bulk matter driven by moving electrons without any (anti-)ferroic order. Notably, current-induced magnetization generates a magnetic field that is not circular around but is parallel to the applied current; thus, this phenomenon opens a new area of magnetic field generation beyond Ampere’s law that may lead to industrial applications.
Identification of catalytic sites in cobalt-nitrogen-carbon materials for the oxygen reduction reaction
Authors: Zitolo Andrea , Ranjbar-Sahraie Nastaran , Mineva Tzonka , Li Jingkun , Jia Qingying , Stamatin Serban , Harrington George F. , Lyth Stephen Mathew , Krtil Petr , Mukerjee Sanjeev , Fonda Emiliano , Jaouen Frédéric
Published: October 2017

Single-atom catalysts with full utilization of metal centers can bridge the gap between molecular and solid-state catalysis. Metal-nitrogen-carbon materials prepared via pyrolysis are promising single-atom catalysts but often also comprise metallic particles. Here, we pyrolytically synthesize a Co–N–C material only comprising atomically dispersed cobalt ions and identify with X-ray absorption spectroscopy, magnetic susceptibility measurements and density functional theory the structure and electronic state of three porphyrinic moieties, CoN4C12, CoN3C10,porp and CoN2C5. The O2 electro-reduction and operando X-ray absorption response are measured in acidic medium on Co–N–C and compared to those of a Fe–N–C catalyst prepared similarly. We show that cobalt moieties are unmodified from 0.0 to 1.0 V versus a reversible hydrogen electrode, while Fe-based moieties experience structural and electronic-state changes. On the basis of density functional theory analysis and established relationships between redox potential and O2-adsorption strength, we conclude that cobalt-based moieties bind O2 too weakly for efficient O2 reduction.
Comprehensive assessment of the safety of olodaterol 5 µg in the Respimat® device for maintenance treatment of COPD: comparison with the long-acting β2-agonist formoterol
Authors: Koch Andrea , Watz Henrik , Maleki-Yazdi M. Reza , Bothner Ulrich , Tetzlaff Kay , Voß Florian , McGarvey Lorcan
Published: October 2017

This analysis provides a comprehensive clinical assessment of the long-term safety of the licensed dose of olodaterol (5 µg once daily [QD] via Respimat® inhaler) in patients with chronic obstructive pulmonary disease by exploring the occurrence of acknowledged side effects of long-acting β2-agonists as well as those included in the olodaterol and formoterol labels. We analysed pooled data from two replicate, double-blind studies of olodaterol (5 µg QD via Respimat®) compared to formoterol (12 µg twice daily [BID]) or placebo over 48 weeks (1222.13, NCT00793624; 1222.14, NCT00796653). Patients could continue their background treatment. The analysis considered adverse events (AEs) typically associated with β2-agonists, including cardiovascular events, as well as administration-related events. Descriptive statistics were provided for the incidence of AEs and aggregated AEs. The analysis included 1379 patients: 460 placebo, 459 olodaterol and 460 formoterol; AEs were reported by 70.9, 71.7 and 69.1% of patients, respectively. Exposure-adjusted incidence rates of cardiac AEs (arrhythmia and myocardial ischaemia) and cough were numerically lower in the olodaterol group than the formoterol group, while nasopharyngitis, throat irritation, metabolism and psychiatric disorders were numerically higher in the olodaterol group. The most frequent event in the olodaterol group was nasopharyngitis (placebo 8.0%; olodaterol 12.9%; formoterol 10.0%). Except for cough (incidence rate ratio of 0.46 [95% confidence interval 0.24, 0.89] in favour of olodaterol), there were no significant differences between active groups. In conclusion, olodaterol 5 µg QD was well tolerated over 48 weeks with a typical β2-agonist safety profile comparable to formoterol 12 µg BID.
Incorporation of tetanus-epitope into virus-like particles achieves vaccine responses even in older recipients in models of psoriasis, Alzheimer’s and cat allergy
Authors: Zeltins Andris , West Jonathan , Zabel Franziska , El Turabi Aadil , Balke Ina , Haas Stefanie , Maudrich Melanie , Storni Federico , Engeroff Paul , Jennings Gary T. , Kotecha Abhay , Stuart David I , Foerster John , Bachmann Martin F.
Published: October 2017

Monoclonal antibodies are widely used to treat non-infectious conditions but are costly. Vaccines could offer a cost-effective alternative but have been limited by sub-optimal T-cell stimulation and/or weak vaccine responses in recipients, for example, in elderly patients. We have previously shown that the repetitive structure of virus-like-particles (VLPs) can effectively bypass self-tolerance in therapeutic vaccines. Their efficacy could be increased even further by the incorporation of an epitope stimulating T cell help. However, the self-assembly and stability of VLPs from envelope monomer proteins is sensitive to geometry, rendering the incorporation of foreign epitopes difficult. We here show that it is possible to engineer VLPs derived from a non human-pathogenic plant virus to incorporate a powerful T-cell-stimulatory epitope derived from Tetanus toxoid. These VLPs (termed CMVTT) retain self-assembly as well as long-term stability. Since Th cell memory to Tetanus is near universal in humans, CMVTT-based vaccines can deliver robust antibody-responses even under limiting conditions. By way of proof of concept, we tested a range of such vaccines against chronic inflammatory conditions (model: psoriasis, antigen: interleukin-17), neurodegenerative (Alzheimer’s, β-amyloid), and allergic disease (cat allergy, Fel-d1), respectively. Vaccine responses were uniformly strong, selective, efficientin vivo, observed even in old mice, and employing low vaccine doses. In addition, randomly ascertained human blood cells were reactive to CMVTT-VLPs, confirming recognition of the incorporated Tetanus epitope. The CMVTT-VLP platform is adaptable to almost any antigen and its features and performance are ideally suited for the design of vaccines delivering enhanced responsiveness in aging populations.
Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines
Authors: Lutz Johannes , Lazzaro Sandra , Habbeddine Mohamed , Schmidt Kim Ellen , Baumhof Patrick , Mui Barbara L. , Tam Ying K. , Madden Thomas D. , Hope Michael J. , Heidenreich Regina , Fotin-Mleczek Mariola
Published: October 2017

mRNA represents a promising new vaccine technology platform with high flexibility in regard to development and production. Here, we demonstrate that vaccines based on sequence optimized, chemically unmodified mRNA formulated in optimized lipid nanoparticles (LNPs) are highly immunogenic and well tolerated in non-human primates (NHPs). Single intramuscular vaccination of NHPs with LNP-formulated mRNAs encoding rabies or influenza antigens induced protective antibody titers, which could be boosted and remained stable during an observation period of up to 1 year. First mechanistic insights into the mode of action of the LNP-formulated mRNA vaccines demonstrated a strong activation of the innate immune response at the injection site and in the draining lymph nodes (dLNs). Activation of the innate immune system was reflected by a transient induction of pro-inflammatory cytokines and chemokines and activation of the majority of immune cells in the dLNs. Notably, our data demonstrate that mRNA vaccines can compete with licensed vaccines based on inactivated virus or are even superior in respect of functional antibody and T cell responses. Importantly, we show that the developed LNP-formulated mRNA vaccines can be used as a vaccination platform allowing multiple, sequential vaccinations against different pathogens. These results provide strong evidence that the mRNA technology is a valid approach for the development of effective prophylactic vaccines to prevent infectious diseases.
Packing topology in crystals of proteins and small molecules: a comparison
Authors: Carugo Oliviero , Blatova Olga A. , Medrish Elena O. , Blatov Vladislav A. , Proserpio Davide M.
Published: October 2017

We compared the topologies of protein and small molecule crystals, which have many common features – both are molecular crystals with intermolecular interactions much weaker than intramolecular interactions. They also have different features – a considerably large fraction of the volume of protein crystals is occupied by liquid water while no room is available to other molecules in small molecule crystals. We analyzed the overall and local topology and performed multilevel topological analyses (with the software package ToposPro) of carefully selected high quality sets of protein and small molecule crystal structures. Given the suboptimal packing of protein crystals, which is due the special shape and size of proteins, it would be reasonable to expect that the topology of protein crystals is different from the topology of small molecule crystals. Surprisingly, we discovered that these two types of crystalline compounds have strikingly similar topologies. This might suggest that molecular crystal formations share symmetry rules independent of molecular dimension.
Role of Mast Cells in clearance of Leishmania through extracellular trap formation
Authors: Naqvi Nilofer , Ahuja Kavita , Selvapandiyan Angamuthu , Dey Ranadhir , Nakhasi Hira , Puri Niti
Published: October 2017

Mast Cells (MCs) are one of the first immune cells encountered by invading pathogens. Their presence in large numbers in the superficial dermis, whereLeishmaniais encountered, suggests that they may play a critical role in immune responses toLeishmania. In this study the interactions ofLeishmania donovani, the causative agent of visceral Leishmaniasis, andLeishmania tropica, the causative agent of cutaneous Leishmaniasis with MCs were studied. Co-culture ofLeishmaniawith Peritoneal Mast Cells (PMCs) from BALB/c mice and Rat Basophilic Leukaemia (RBL-2H3) MCs led to significant killing ofL. tropicaand to a lesser extent ofL. donovani. Also, while there was significant uptake ofL. tropicaby MCs,L. donovaniwas not phagocytosed. There was significant generation of Reactive Oxygen Species (ROS) by MCs on co-culture with these species ofLeishmaniawhich may contribute to their clearance. Interactions of MCs withLeishmanialed to generation of MC extracellular traps comprising of DNA, histones and tryptase probably to ensnare these pathogens. These results clearly establish that MCs may contribute to host defences toLeishmaniain a differential manner, by actively taking up these pathogens, and also by mounting effector responses for their clearance by extracellular means.
Experimental investigation on the geometry of GHZ states
Authors: Carvacho Gonzalo , Graffitti Francesco , D’Ambrosio Vincenzo , Hiesmayr Beatrix C. , Sciarrino Fabio
Published: October 2017

Greenberger-Horne-Zeilinger (GHZ) states and their mixtures exhibit fascinating properties. A complete basis of GHZ states can be constructed by properly choosing local basis rotations. We demonstrate this experimentally for the Hilbert space $${{\mathbb{C}}}_{2}^{\otimes 4}$$

ℂ

2

⊗
4

by entangling two photons in polarization and orbital angular momentum. Mixing GHZ states unmasks different entanglement features based on their particular local geometrical connectedness. In particular, a specific GHZ state in a complete orthonormal basis has a “twin” GHZ state for which equally mixing leads to full separability in opposition to any other basis-state. Exploiting these local geometrical relations provides a toolbox for generating specific types of multipartite entanglement, each providing different benefits in outperforming classical devices. Our experiment investigates these GHZ’s properties exploiting the HMGH framework which allows us to study the geometry for the different depths of entanglement in our system and showing a good stability and fidelity thus admitting a scaling in degrees of freedom and advanced operational manipulations.
Visuo-acoustic stimulation that helps you to relax: A virtual reality setup for patients in the intensive care unit
Authors: Gerber Stephan M. , Jeitziner Marie-Madlen , Wyss Patric , Chesham Alvin , Urwyler Prabitha , Müri René M. , Jakob Stephan M. , Nef Tobias
Published: October 2017

After prolonged stay in an intensive care unit (ICU) patients often complain about cognitive impairments that affect health-related quality of life after discharge. The aim of this proof-of-concept study was to test the feasibility and effects of controlled visual and acoustic stimulation in a virtual reality (VR) setup in the ICU. The VR setup consisted of a head-mounted display in combination with an eye tracker and sensors to assess vital signs. The stimulation consisted of videos featuring natural scenes and was tested in 37 healthy participants in the ICU. The VR stimulation led to a reduction of heart rate (p = 0. 049) and blood pressure (p = 0.044). Fixation/saccade ratio (p < 0.001) was increased when a visual target was presented superimposed on the videos (reduced search activity), reflecting enhanced visual processing. Overall, the VR stimulation had a relaxing effect as shown in vital markers of physical stress and participants explored less when attending the target. Our study indicates that VR stimulation in ICU settings is feasible and beneficial for critically ill patients.
Phenotyping of autoreactive B cells with labeled nucleosomes in 56R transgenic mice
Authors: Gies Vincent , Bouis Delphine , Martin Mickaël , Pasquali Jean-L. , Martin Thierry , Korganow Anne-S. , Soulas-Sprauel Pauline
Published: October 2017

The phenotypic characterization of self-reactive B cells producing autoantibodies is one of the challenges to get further insight in the physiopathology of autoimmune diseases. We took advantage of our previously developed flow cytometry method, using labeled nucleosomes, prominent autoantigens in systemic lupus erythematosus, to analyze the phenotype of self-reactive B cells in the anti-DNA B6.56R mouse model. We showed that splenic anti-nucleosome B cells express mostly kappa light chains and harbor a marginal zone phenotype. Moreover, these autoreactive B cells fail to acquire a germinal center phenotype and are less abundant in the transitional T3 compartment. In conclusion, the direct detection of autoreactive B cells helped determine their phenotypic characteristics and provided a more direct insight into the B cell tolerance process in B6.56R mice. This method constitutes an interesting new tool to study the mechanisms of B cell tolerance breakdown in B6.56R mice crossed with autoimmune prone models.
A method to determine pharmacokinetic parameters based on andante constant-rate intravenous infusion
Authors: Yu Rui-hong , Cao Yong-xiao
Published: October 2017

On account of the disturbance from the distribution phase, the concentration-time curve of drugs cannot fully reflect the characteristics of elimination, and thus, it is difficult for present methods to obtain ideal pharmacokinetic parameters. This paper presents a method to determine pharmacokinetic parameters based on an andante constant-rate intravenous infusion. A mathematical model of the constant-rate intravenous infusion combined with the elimination of first-order kinetics was established. During infusion, the accumulation tendency of drugs was deduced as $${C}_{t}={C}_{{0}}+({C}_{ss}-{C}_{{0}})\cdot (1-{e}^{-Kt})$$

C

t

=

C

0

+
(

C

s
s

−

C

0

)
⋅
(
1
−

e

−
K
t

)
using the principle of calculus. Then, the method to determine the pharmacokinetic parameters was summed up. After collecting the blood drug concentration (C
t
) -time (t) data from a constant-rate (v) infusion period, an exponential regression analysis was conducted to obtain the elimination rate constant (K) and plateau concentration (C
ss
). Then, the half-life (t
1/2
), apparent volume of distribution (V
d
) and clearance rate (CL) were calculated based on the equations, t
1/2
 = 0.693/K, V
d
 = (v/K)/C
ss
and CL = v/C
ss
, respectively. In addition, an application example of cimetidine in a beagle dog was used to demonstrate the implementation process of the method.
Pro-angiogenic effect of RANTES-loaded polysaccharide-based microparticles for a mouse ischemia therapy
Authors: Suffee N. , Le Visage C. , Hlawaty H. , Aid-Launais R. , Vanneaux V. , Larghero J. , Haddad O. , Oudar O. , Charnaux N. , Sutton A.
Published: October 2017

Peripheral arterial disease results from the chronic obstruction of arteries leading to critical hindlimb ischemia. The aim was to develop a new therapeutic strategy of revascularization by using biodegradable and biocompatible polysaccharides-based microparticles (MP) to treat the mouse hindlimb ischemia. For this purpose, we deliver the pro-angiogenic chemokine Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES)/CCL5 in the mouse ischemic hindlimb, in solution or incorporated into polysaccharide-based microparticles. We demonstrate that RANTES-loaded microparticles improve the clinical score, induce the revascularization and the muscle regeneration in injured mice limb. To decipher the mechanisms underlying RANTES effects in vivo, we demonstrate that RANTES increases the spreading, the migration of human endothelial progenitor cells (EPC) and the formation of vascular network. The main receptors of RANTES i.e. CCR5, syndecan-4 and CD44 expressed at endothelial progenitor cell surface are involved in RANTES-induced in vitro biological effects on EPC. By using two RANTES mutants, [E66A]-RANTES with impaired ability to oligomerize, and [44AANA47]-RANTES mutated in the main RANTES-glycosaminoglycan binding site, we demonstrate that both chemokine oligomerization and binding site to glycosaminoglycans are essential for RANTES-induced angiogenesis in vitro. Herein we improved the muscle regeneration and revascularization after RANTES-loaded MP local injection in mice hindlimb ischemia.
A comparative study of machine learning methods for time-to-event survival data for radiomics risk modelling
Authors: Leger Stefan , Zwanenburg Alex , Pilz Karoline , Lohaus Fabian , Linge Annett , Zöphel Klaus , Kotzerke Jörg , Schreiber Andreas , Tinhofer Inge , Budach Volker , Sak Ali , Stuschke Martin , Balermpas Panagiotis , Rödel Claus , Ganswindt Ute , Belka Claus , Pigorsch Steffi , Combs Stephanie E. , Mönnich David , Zips Daniel , Krause Mechthild , Baumann Michael , Troost Esther G. C. , Löck Steffen , Richter Christian
Published: October 2017

Radiomics applies machine learning algorithms to quantitative imaging data to characterise the tumour phenotype and predict clinical outcome. For the development of radiomics risk models, a variety of different algorithms is available and it is not clear which one gives optimal results. Therefore, we assessed the performance of 11 machine learning algorithms combined with 12 feature selection methods by the concordance index (C-Index), to predict loco-regional tumour control (LRC) and overall survival for patients with head and neck squamous cell carcinoma. The considered algorithms are able to deal with continuous time-to-event survival data. Feature selection and model building were performed on a multicentre cohort (213 patients) and validated using an independent cohort (80 patients). We found several combinations of machine learning algorithms and feature selection methods which achieve similar results, e.g., MSR-RF: C-Index = 0.71 and BT-COX: C-Index = 0.70 in combination with Spearman feature selection. Using the best performing models, patients were stratified into groups of low and high risk of recurrence. Significant differences in LRC were obtained between both groups on the validation cohort. Based on the presented analysis, we identified a subset of algorithms which should be considered in future radiomics studies to develop stable and clinically relevant predictive models for time-to-event endpoints.
Importance of interlayer H bonding structure to the stability of layered minerals
Authors: Conroy Michele , Soltis Jennifer A. , Wittman Rick S. , Smith Frances N. , Chatterjee Sayandev , Zhang Xin , Ilton Eugene S. , Buck Edgar C.
Published: October 2017

Layered (oxy) hydroxide minerals often possess out-of-plane hydrogen atoms that form hydrogen bonding networks which stabilize the layered structure. However, less is known about how the ordering of these bonds affects the structural stability and solubility of these minerals. Here, we report a new strategy that uses the focused electron beam to probe the effect of differences in hydrogen bonding networks on mineral solubility. In this regard, the dissolution behavior of boehmite (γ-AlOOH) and gibbsite (γ-Al(OH)3) were compared and contrasted in real time via liquid cell electron microscopy. Under identical such conditions, 2D-nanosheets of boehmite (γ-AlOOH) exfoliated from the bulk and then rapidly dissolved, whereas gibbsite was stable. Further, substitution of only 1% Fe(III) for Al(III) in the structure of boehmite inhibited delamination and dissolution. Factors such as pH, radiolytic species, and knock on damage were systematically studied and eliminated as proximal causes for boehmite dissolution. Instead, the creation of electron/hole pairs was considered to be the mechanism that drove dissolution. The widely disparate behaviors of boehmite, gibbsite, and Fe-doped boehmite are discussed in the context of differences in the OH bond strengths, hydrogen bonding networks, and the presence or absence of electron/hole recombination centers.
Haplotype analysis of XRCC2 gene polymorphisms and association with increased risk of head and neck cancer
Authors: Saeed Soma , Mahjabeen Ishrat , Sarwar Romana , Bashir Kashif , Kayani Mahmood Akhtar
Published: October 2017

We aimed to investigate the effect of hotspot variations of XRCC2 gene on the risk of head and neck cancer (HNC) in 400 patients and 400 controls. Five polymorphisms of XRCC2 gene G4234C (rs3218384), G4088T (rs3218373), G3063A (rs2040639), R188H (rs3218536) and rs7802034 were analyzed using Allele- specific polymerase chain reaction (ARMS-PCR) followed by sequence analysis. For rs3218373, the GG genotype indicated a statistically significant 3-fold increased risk of HNC (P < 0.001) after multivariate adjustment. For rs7802034, the GG genotype suggested statistically significant 2-fold increased risk of HNC (P < 0.001). For SNP of rs3218536, the AA genotype indicated a significant 3-fold increased risk of HNC (P < 0.001). Additionally, haplotype analysis revealed that TACAG, TGGAG, TACGG and TAGGA haplotypes of XRCC2 polymorphisms are associated with HNC risk. Two SNPs in XRCC2 (rs2040639 and rs3218384) were found increased in strong linkage disequilibrium. Furthermore, joint effect model showed 20 fold (OR = 19.89; 95% CI = 2.65–149.36, P = 0.003) increased HNC risk in patients carrying four homozygous risk alleles of selected polymorphisms. These results show that allele distributions and genotypes of XRCC2 SNPs are significantly associated with increased HNC risk and could be a genetic adjuster for the said disease.
A quantitative comparison of cytosolic delivery via different protein uptake systems
Authors: Verdurmen Wouter P. R. , Mazlami Marigona , Plückthun Andreas
Published: October 2017

Over many years, a variety of delivery systems have been investigated that have the capacity to shuttle macromolecular cargoes, especially proteins, into the cytosol. Due to the lack of an objective way to quantify cytosolic delivery, relative delivery efficiencies of the various transport systems have remained unclear. Here, we demonstrate the use of the biotin ligase assay for a quantitative comparison of protein transport to the cytosol via cell-penetrating peptides, supercharged proteins and bacterial toxins in four different cell lines. The data illustrate large differences in both the total cellular internalization, which denotes any intracellular location including endosomes, and in the cytosolic uptake of the transport systems, with little correlation between the two. Also, we found significant differences between the cell lines. In general, protein transport systems based on cell-penetrating peptides show a modest total uptake, and mostly do not deliver cargo to the cytosol. Systems based on bacterial toxins show a modest receptor-mediated internalization but an efficient delivery to the cytosol. Supercharged proteins, on the contrary, are not receptor-specific and lead to massive total internalization into endosomes, but only low amounts end up in the cytosol.
Stabilization of mouse haploid embryonic stem cells with combined kinase and signal modulation
Authors: Li Haisen , Guo Ao , Xie Zhenfei , Tu Wanzhi , Yu Jiali , Wang Huihan , Zhao Jian , Zhong Cuiqing , Kang Jiuhong , Li Jinsong , Huang Shichao , Shen Li
Published: October 2017

Mammalian haploid embryonic stem cells (haESCs) provide new possibilities for large-scale genetic screens because they bear only one copy of each chromosome. However, haESCs are prone to spontaneous diploidization through unknown mechanisms. Here, we report that a small molecule combination could restrain mouse haESCs from diploidization by impeding exit from naïve pluripotency and by shortening the S-G2/M phases. Combined with 2i and PD166285, our chemical cocktail could maintain haESCs in the haploid state for at least five weeks without fluorescence-activated cell sorting (FACS) enrichment of haploid cells. Taken together, we established an effective chemical approach for long-term maintenance of haESCs, and highlighted that proper cell cycle progression was critical for the maintenance of haploid state.