bluuebunny/crossref_metadata_2025 huggingface dataset:
2-Deoxy-D-Glucose inhibits aggressive triple-negative breast cancer cells by targeting glycolysis and the cancer stem cell phenotype
Authors: O’Neill Sadhbh , Porter Richard K. , McNamee Niamh , Martinez Vanesa G. , O’Driscoll Lorraine
Published: March 2019

Due to limited availability of pharmacological therapies, triple-negative breast cancer (TNBC) is the subtype with worst outcome. We hypothesised that 2-Deoxy-D-Glucose (2-DG), a glucose analogue, may hold potential as a therapy for particularly aggressive TNBC. We investigated 2-DG’s effects on TNBC cell line variants, Hs578T parental cells and their isogenic more aggressive Hs578Ts(i)8 variant, using migration, invasion and anoikis assays. We assessed their bioenergetics by Seahorse. We evaluated metabolic alterations using a Seahorse XF Analyzer, citrate synthase assay, immunoblotting and flow cytometry. We assessed the cancer stem cell (CSC) phenotype of the variants and 2-DG’s effects on CSCs. 2-DG significantly inhibited migration and invasion of Hs578Ts(i)8 versus Hs578T and significantly decreased their ability to resist anoikis. Investigating 2-DG’s preferential inhibitory effect on the more aggressive cells, we found Hs578Ts(i)8 also had significantly decreased oxidative phosphorylation and increased glycolysis compared to Hs578T. This is likely due to mitochondrial dysfunction in Hs578Ts(i)8, shown by their significantly decreased mitochondrial membrane potential. Furthermore, Hs578Ts(i)8 had a significantly increased proportion of cells with CSC phenotype, which was significantly decreased by 2-DG. 2-DG may have benefit as a therapy for TNBC with a particularly aggressive phenotype, by targeting increased glycolysis. Studies of more cell lines and patients’ specimens are warranted.
Modelling the impact of effective private provider engagement on tuberculosis control in urban India
Authors: Arinaminpathy Nimalan , Deo Sarang , Singh Simrita , Khaparde Sunil , Rao Raghuram , Vadera Bhavin , Kulshrestha Niraj , Gupta Devesh , Rade Kiran , Nair Sreenivas Achuthan , Dewan Puneet
Published: March 2019

In India, the country with the world’s largest burden of tuberculosis (TB), most patients first seek care in the private healthcare sector, which is fragmented and unregulated. Ongoing initiatives are demonstrating effective approaches for engaging with this sector, and form a central part of India’s recent National Strategic Plan: here we aimed to address their potential impact on TB transmission in urban settings, when taken to scale. We developed a mathematical model of TB transmission dynamics, calibrated to urban populations in Mumbai and Patna, two major cities in India where pilot interventions are currently ongoing. We found that, when taken to sufficient scale to capture 75% of patient-provider interactions, the intervention could reduce incidence by upto 21.3% (95% Bayesian credible interval (CrI) 13.0–32.5%) and 15.8% (95% CrI 7.8–28.2%) in Mumbai and Patna respectively, between 2018 and 2025. There is a stronger impact on TB mortality, with a reduction of up to 38.1% (95% CrI 20.0–55.1%) in the example of Mumbai. The incidence impact of this intervention alone may be limited by the amount of transmission that has already occurred by the time a patient first presents for care: model estimates suggest an initial patient delay of 4–5 months before first seeking care, followed by a diagnostic delay of 1–2 months before ultimately initiating TB treatment. Our results suggest that the transmission impact of such interventions could be maximised by additional measures to encourage early uptake of TB services.
Dental pulp cell-derived powerful inducer of TNF-α comprises PKR containing stress granule rich microvesicles
Authors: Suzuki Shigeki , Fukuda Takao , Nagayasu Shintaro , Nakanishi Jun , Yoshida Kazuma , Hirata-Tsuchiya Shizu , Nakao Yuki , Sano Tomomi , Yamashita Akiko , Yamada Satoru , Ohta Kouji , Shiba Hideki , Nishimura Fusanori
Published: March 2019

It is well known that dental pulp tissue can evoke some of the most severe acute inflammation observed in the human body. We found that dental pulp cells secrete a factor that induces tumor necrosis factor-α production from macrophages, and designated this factor, dental pulp cell-derived powerful inducer of TNF-α (DPIT). DPIT was induced in dental pulp cells and transported to recipient cells via microvesicles. Treatment of dental pulp cells with a PKR inhibitor markedly suppressed DPIT activity, and weak interferon signals were constitutively activated inside the cells. In recipient macrophages, stimulation with DPIT-containing supernatants from pulp cells resulted in activation of both nuclear factor-κB and MAP kinases like JNK and p38. Proteomics analyses revealed that many stress granule-related proteins were present in supernatants from dental pulp cells as well as microvesicle marker proteins like GAPDH, β-actin, HSPA8, HSPB1, HSPE1, and HSPD1. Furthermore, giant molecule AHNAK and PKR were detected in microvesicles derived from dental pulp cells, and gene silencing of AHNAK in dental pulp cells led to reduced DPIT activity. Thus, it appeared that the core protein of DPIT was PKR, and that PKR was maintained in an active state in stress granule aggregates with AHNAK and transported via microvesicles. The activity of DPIT for TNF-α induction was far superior to that of gram-negative bacterial endotoxin. Therefore, we, report for the first time, that active PKR is transported via microvesicles as stress granule aggregates and induces powerful inflammatory signals in macrophages.
Emergency Department Visits and Disease Burden Attributable to Ambulatory Care Sensitive Conditions in Elderly Adults
Authors: Hsieh Vivian Chia-Rong , Hsieh Meng-Lun , Chiang Jen-Huai , Chien Andy , Hsieh Ming-Shun
Published: March 2019

Many countries worldwide are aging rapidly, and the complex care needs of older adults generate an unprecedented demand for health services. Common reasons for elderly emergency department (ED) visits frequently involve conditions triggered by preventable infections also known as ambulatory care sensitive conditions (ACSCs). This study aims to describe the trend and the associated disease burden attributable to ACSC-related ED visits made by elderly patients and to characterize their ED use by nursing home residence. We designed a population-based ecological study using administrative data on Taiwan EDs between 2002 and 2013. A total of 563,647 ED visits from individuals aged 65 or over were examined. All elderly ED visits due to ACSCs (tuberculosis, upper respiratory infection, pneumonia, sepsis, cellulitis and urinary tract infection (UTI)) were further identified. Subsequent hospital admissions, related deaths after discharge, total health care costs and disability-adjusted life years (DALYs) were compared among different ACSCs. Prevalence of ACSCs was then assessed between nursing home (NH) residents and non-NH residents. Within the 12-year observation period, we find that there was a steady increase in both the rate of ACSC ED visits and the proportion of elderly with a visit. Overall, pneumonia is the most prevalent among six ACSCs for elderly ED visits (2.10%; 2.06 to 2.14), subsequent hospital admissions (5.77%; 5.59 to 5.94) and associated mortality following admission (17.37%; 16.74 to 18.01). UTI is the second prevalent ACSC consistently across ED visits (2.02%; 1.98 to 2.05), subsequent hospital admissions (2.36%, 2.25 to 2.48) and mortality following admission (10.80%; 10.28 to 11.32). Sepsis ranks third highest in the proportion of hospitalization following ED visit (2.29%; 2.18 to 2.41) and related deaths after hospital discharge (7.39%; 6.95 to 7.83), but it accounts for the highest average total health care expenditure (NT$94,595 ± 120,239; ≈US$3185.02) per case. When examining the likelihood of ACSC-attributable ED use, significantly higher odds were observed in NH residents as compared with non-NH residents for: pneumonia (adjusted odds ratio (aOR): 5.01, 95% confidence interval (CI) 4.50–5.58); UTI (aOR: 4.44, 95% CI 3.97–4.98); sepsis (aOR: 3.54, 95% CI 3.06–4.10); and tuberculosis (aOR: 2.44, 95% CI 1.63–3.65). Here we examined the ACSC-related ED care and found that, among the six ACSCs studied, pneumonia, UTI and sepsis were the leading causes of ED visits, subsequent hospital admissions, related mortality, health care costs and DALYs in Taiwanese NH elderly adults. Our findings suggest that efficient monitoring and reinforcing of quality of care in the residential and community setting might substantially reduce the number of preventable elderly ED visits and alleviate strain on the health care system.
Recrystallization as the governing mechanism of ion track formation
Authors: Rymzhanov R. A. , Medvedev N. , O’Connell J. H. , Janse van Vuuren A. , Skuratov V. A. , Volkov A. E.
Published: March 2019

Response of dielectric crystals: MgO, Al2O3 and Y3Al5O12 (YAG) to irradiation with 167 MeV Xe ions decelerating in the electronic stopping regime is studied. Comprehensive simulations demonstrated that despite similar ion energy losses and the initial excitation kinetics of the electronic systems and lattices, significant differences occur among final structures of ion tracks in these materials, supported by experiments. No ion tracks appeared in MgO, whereas discontinuous distorted crystalline tracks of ~2 nm in diameter were observed in Al2O3 and continuous amorphous tracks were detected in YAG. These track structures in Al2O3 and YAG were confirmed by high resolution TEM data. The simulations enabled us to identify recrystallization as the dominant mechanism governing formation of detected tracks in these oxides. We analyzed effects of the viscosity in molten state, lattice structure and difference in the kinetics of metallic and oxygen sublattices at the crystallization surface on damage recovery in tracks.
Species distribution and antifungal drug susceptibilities of yeasts isolated from the blood samples of patients with candidemia
Authors: Lindberg Erika , Hammarström Helena , Ataollahy Nasser , Kondori Nahid
Published: March 2019

Candida albicans is the most frequently isolated fungal species in hospital settings worldwide. However, non-albicans Candida species with decreased susceptibility to antifungals have emerged as an important cause of fungemia. The aims of this study were to determine the species distribution of fungi isolated from the blood samples of patients at a Swedish University Hospital and to define the in vitro susceptibilities of these isolates to nine antifungal agents. In total, 233 yeast isolates from 143 patients were included in this study. Antifungal susceptibility testing was performed using broth dilution Sensititre YeastOne panels, which comprised amphotericin B, 5-flucytosine, fluconazole, itraconazole, voriconazole, posaconazole, anidulafungin, micafungin, and caspofungin. The most common species in all age groups was C. albicans (n = 93, 65%), followed by C. glabrata (n = 27, 19%) and C. parapsilosis (n = 15, 10%). C. glabrata was mostly found in elderly individuals, while C. parapsilosis was found mainly in young children (p = 0.008). Antifungal resistance was low in the Candida species, except for reduced susceptibility to fluconazole among C. glabrata strains. C. albicans is the most frequent colonizer of Swedish patients. In general antifungal resistance is uncommon in Candida species. Nevertheless, reduced susceptibilities to fluconazole and echinocandins were found in C. glabrata and C. parapsilosis, respectively.
CT Scanning and MATLAB Calculations for Preservation of Coptic Mural Paintings in Historic Egyptian Monasteries
Authors: Sallam Ahmed , Hemeda Sayed , Toprak Muhammet S. , Muhammed Mamoun , Hassan Moustapha , Uheida Abdusalam
Published: March 2019

Investigations of Coptic mural paintings in historic churches and monasteries demand a deep understanding of the micro structure of the mural painting layers. The main objective of the present study is to study the efficiency of new avenues of computed X-ray tomography (CT Scan) and MATLAB in the analysis of Coptic mural paintings, either in the form of images or videos made to collect information about the physical characteristics of the material structure of the layers of mural paintings. These advanced techniques have been used in the investigation of samples of Coptic mural paintings dating back to the V–VIII century A.D, which have been collected from several locations in the Coptic monasteries in Upper Egypt. The application of CT-scanning is a powerful non-destructive tool for imaging and investigation which can be applied to the preservation of monuments made from many different materials. The second stage of research will be to characterize the materials through analytical techniques including XRD, XRF, EDX and FTIR to confirm the findings of CT scanning and to provide additional information concerning the materials used and their deterioration processes. This paper presents the results of the first pilot study in which CT scan and MATLAB have been utilized in combination for the non-destructive evaluation and investigation of Coptic mural paintings in Upper Egypt. The examinations have been carried out on mural painting samples from three important Coptic monasteries in Upper Egypt: the Qubbat Al Hawa Monastery in Aswan, the Saint Simeon Monastery in Aswan and the Saint Matthew the Potter Monastery in Luxor. This multi-stranded investigation has provided us with important information about the physical structure of the paintings, grains dimensions, grain texture, pore media characterization which include the micro porosity, BET and TPV, surface rendering, and calculation of the points in the surface through calculations completed using MATLAB. CT scanning assisted in the investigation and analyses of image surface details, and helped to visualize hidden micro structures that would otherwise be inaccessible due to over painting.
Distinct mechanisms of temporal binding in generalized and cross-modal flash-lag effects
Authors: Hayashi Ryusuke , Murakami Ikuya
Published: March 2019

It remains unknown how the brain temporally binds sensory data across different modalities and attributes to create coherent perceptual experiences. To address this question, we measured what we see at the time we experience an event using a generalized version of the flash-lag effect (FLE) for combinations of visual attribute (bar orientation, face orientation, or face identity) and probe modality (visual or auditory). We asked participants to judge the content of rapidly and serially presented images seen at the same time as a briefly presented visual (flash) or auditory (click) probe and estimated the “time windows” contributing to decisions using reverse correlation analysis. We also used displays in which the visual attribute of a stimulus continuously changed and measured FLEs around abrupt flip in change direction and at the initiation and termination of a sequence. We consistently found clear latency-difference effects, which depended on visual attribute for the visual probe but did not for the auditory probe. The intra-modal FLE can be explained in terms of differential latency and temporal integration, but the cross-modal FLE is suggested to operate via a distinct mechanism; the content of a successive visual stream experienced after the awareness of a click is interpreted as simultaneous with the click.
Identification of CD4 and H-2Kd-restricted cytotoxic T lymphocyte epitopes on the human herpesvirus 6B glycoprotein Q1 protein
Authors: Nagamata Satoshi , Aoshi Taiki , Kawabata Akiko , Yamagishi Yoshiaki , Nishimura Mitsuhiro , Kuwabara Soichiro , Murakami Kouki , Yamada Hideto , Mori Yasuko
Published: March 2019

The identification of Human herpesvirus 6B (HHV-6B) epitopes that are recognized by T-cells could contribute to the development of potential vaccines and immunotherapies. Here, we identified CD4+and H-2Kd-restricted CD8+T-cell epitopes on the glycoprotein Q1 of HHV-6B (BgQ1), which is a unique glycoprotein and essential for HHV-6B viral entry, by usingin vivoelectroporation with a plasmid DNA encoding BgQ1, overlapping peptides spanning the BgQ1 sequence, ELISPOT assay for quantification of gamma interferon (IFN-γ), and computer-based T-cell epitope prediction programs. The CD4+and CD8+T-cell epitopes identified in BALB/c mice in this study could be a good animal model system for use in the development of T-cell responses, inducing HHV-6B vaccines or immunotherapies.
Histamine modulation of urinary bladder urothelium, lamina propria and detrusor contractile activity via H1 and H2 receptors
Authors: Stromberga Zane , Chess-Williams Russ , Moro Christian
Published: March 2019

The mechanisms underlying bladder contractile disorders such as overactive bladder are not fully understood, and there is limited understanding of the receptor systems modulating spontaneous bladder contractions. We investigated the potential for histamine to have a role in mediating contractility of the urothelium with lamina propria (U&LP) or detrusor via the H1-H4 histamine receptor subtypes. Isolated strips of porcine U&LP or detrusor smooth muscle were mounted in gassed Krebs-bicarbonate solution and responses to histamine obtained in the absence and presence of selective receptor antagonists. The presence of histamine increases the frequency of U&LP spontaneous phasic contractions and baseline tensions. In response to histamine, H1-antagonists pyrilamine, fexofenadine and cyproheptadine were effective at inhibiting contractile responses. Cimetidine (H2-antagonist) enhanced increases in baseline tension in response histamine, whereas amthamine (H2-agonist) induced relaxation. Although thioperamide (H3/H4-antagonist) increased baseline tension responses to histamine, selective H1/H2-receptor antagonism revealed no influence of these receptors. In detrusor preparations, pyrilamine, fexofenadine and cyproheptadine were effective at inhibiting baseline tension increases in response to histamine. Our findings provide evidence that histamine produces contractile responses both in the U&LP and detrusor via the H1-receptor, and this response is significantly inhibited by activation of the H2-receptor in the U&LP but not the detrusor.
Modular structure, sequence diversification and appropriate nomenclature of seroins produced in the silk glands of Lepidoptera
Authors: Kucerova Lucie , Zurovec Michal , Kludkiewicz Barbara , Hradilova Miluse , Strnad Hynek , Sehnal Frantisek
Published: March 2019

Seroins are small lepidopteran silk proteins known to possess antimicrobial activities. Several seroin paralogs and isoforms were identified in studied lepidopteran species and their classification required detailed phylogenetic analysis based on complete and verified cDNA sequences. We sequenced silk gland-specific cDNA libraries from ten species and identified 52 novel seroin cDNAs. The results of this targeted research, combined with data retrieved from available databases, form a dataset representing the major clades of Lepidoptera. The analysis of deduced seroin proteins distinguished three seroin classes (sn1-sn3), which are composed of modules: A (includes the signal peptide), B (rich in charged amino acids) and C (highly variable linker containing proline). The similarities within and between the classes were 31–50% and 22.5–25%, respectively. All species express one, and in exceptional cases two, genes per class, and alternative splicing further enhances seroin diversity. Seroins occur in long versions with the full set of modules (AB1C1B2C2B3) and/or in short versions that lack parts or the entire B and C modules. The classes and the modular structure of seroins probably evolved prior to the split between Trichoptera and Lepidoptera. The diversity of seroins is reflected in proposed nomenclature.
Functional characterization of iPSC-derived arterial- and venous-like endothelial cells
Authors: Rosa S. , Praça C. , Pitrez P. R. , Gouveia P. José , Aranguren X. L. , Ricotti L. , Ferreira L. Silva
Published: March 2019

The current work reports the functional characterization of human induced pluripotent stem cells (iPSCs)- arterial and venous-like endothelial cells (ECs), derived in chemically defined conditions, either in monoculture or seeded in a scaffold with mechanical properties similar to blood vessels. iPSC-derived arterial- and venous-like endothelial cells were obtained in two steps: differentiation of iPSCs into endothelial precursor cells (CD31pos/KDRpos/VE-Cadmed/EphB2neg/COUP-TFneg) followed by their differentiation into arterial and venous-like ECs using a high and low vascular endothelial growth factor (VEGF) concentration. Cells were characterized at gene, protein and functional levels. Functionally, both arterial and venous-like iPSC-derived ECs responded to vasoactive agonists such as thrombin and prostaglandin E2 (PGE2), similar to somatic ECs; however, arterial-like iPSC-derived ECs produced higher nitric oxide (NO) and elongation to shear stress than venous-like iPSC-derived ECs. Both cells adhered, proliferated and prevented platelet activation when seeded in poly(caprolactone) scaffolds. Interestingly, both iPSC-derived ECs cultured in monoculture or in a scaffold showed a different inflammatory profile than somatic ECs. Although both somatic and iPSC-derived ECs responded to tumor necrosis factor-α (TNF-α) by an increase in the expression of intercellular adhesion molecule 1 (ICAM-1), only somatic ECs showed an upregulation in the expression of E-selectin or vascular cell adhesion molecule 1 (VCAM-1).
Biogeography of Soil Bacterial Networks along a Gradient of Cropping Intensity
Authors: Karimi Battle , Dequiedt Samuel , Terrat Sébastien , Jolivet Claudy , Arrouays Dominique , Wincker Patrick , Cruaud Corinne , Bispo Antonio , Chemidlin Prévost-Bouré Nicolas , Ranjard Lionel
Published: March 2019

Although land use drives soil bacterial diversity and community structure, little information about the bacterial interaction networks is available. Here, we investigated bacterial co-occurrence networks in soils under different types of land use (forests, grasslands, crops and vineyards) by sampling 1798 sites in the French Soil Quality Monitoring Network covering all of France. An increase in bacterial richness was observed from forests to vineyards, whereas network complexity respectively decreased from 16,430 links to 2,046. However, the ratio of positive to negative links within the bacterial networks ranged from 2.9 in forests to 5.5 in vineyards. Networks structure was centered on the most connected genera (called hub), which belonged toBacteroidetesin forest and grassland soils, but toActinobacteriain vineyard soils. Overall, our study revealed that soil perturbation due to intensive cropping reduces strongly the complexity of bacterial network although the richness is increased. Moreover, the hub genera within the bacterial community shifted from copiotrophic taxa in forest soils to more oligotrophic taxa in agricultural soils.
Secondary structure of the segment 5 genomic RNA of influenza A virus and its application for designing antisense oligonucleotides
Authors: Michalak Paula , Soszynska-Jozwiak Marta , Biala Ewa , Moss Walter N. , Kesy Julita , Szutkowska Barbara , Lenartowicz Elzbieta , Kierzek Ryszard , Kierzek Elzbieta
Published: March 2019

Influenza virus causes seasonal epidemics and dangerous pandemic outbreaks. It is a single stranded (−)RNA virus with a segmented genome. Eight segments of genomic viral RNA (vRNA) form the virion, which are then transcribed and replicated in host cells. The secondary structure of vRNA is an important regulator of virus biology and can be a target for finding new therapeutics. In this paper, the secondary structure of segment 5 vRNA is determined based on chemical mapping data, free energy minimization and structure-sequence conservation analysis for type A influenza. The revealed secondary structure has circular folding with a previously reported panhandle motif and distinct novel domains. Conservations of base pairs is 87% on average with many structural motifs that are highly conserved. Isoenergetic microarray mapping was used to additionally validate secondary structure and to discover regions that easy bind short oligonucleotides. Antisense oligonucleotides, which were designed based on modeled secondary structure and microarray mapping, inhibit influenza A virus proliferation in MDCK cells. The most potent oligonucleotides lowered virus titer by ~90%. These results define universal for type A structured regions that could be important for virus function, as well as new targets for antisense therapeutics.
Ensemble-based analysis of the pollutant spreading intensity induced by climate change
Authors: Haszpra Tímea , Herein Mátyás
Published: March 2019

The intensity of the atmospheric large-scale spreading can be characterized by a measure of chaotic systems, called topological entropy. A pollutant cloud stretches in an exponential manner in time, and in the atmospheric context the topological entropy corresponds to the stretching rate of its length. To explore the plethora of possible climate evolutions, we investigate here pollutant spreading in climate realizations of two climate models to learn what the typical spreading behavior is over a climate change. An overall decrease in the areal mean of the stretching rate is found to be typical in the ensembles of both climate models. This results in larger pollutant concentrations for several geographical regions implying higher environmental risk. A strong correlation is found between the time series of the ensemble mean values of the stretching rate and of the absolute value of the relative vorticity. Here we show that, based on the obtained relationship, the typical intensity of the spreading in an arbitrary climate realization can be estimated by using only the ensemble means of the relative vorticity data of a climate model.
Shape fidelity and structure of 3D printed high consistency nanocellulose
Authors: Klar Ville , Pere Jaakko , Turpeinen Tuomas , Kärki Pyry , Orelma Hannes , Kuosmanen Petri
Published: March 2019

The aim of the present study was to investigate the additive manufacturing process for high consistency nanocellulose. Unlike thermoformable plastics, wood derived nanocelluloses are typically processed as aqueous dispersions because they are not melt-processable on their own. The ability to use nanocellulose directly in additive manufacturing broadens the possibilities regarding usable raw materials and achievable properties thereof. Modern additive manufacturing systems are capable of depositing nanocellulose with micrometer precision, which enables the printing of accurate three-dimensional wet structures. Typically, these wet structures are produced from dilute aqueous fibrillar dispersions. As a consequence of the high water content, the structures deform and shrink during drying unless the constructs are freeze-dried. While freeze-drying preserves the geometry, it results in high porosity which manifests as poor mechanical and barrier properties. Herein, we study an additive manufacturing process for high consistency enzymatically fibrillated cellulose nanofibers in terms of printability, shape retention, structure, and mechanical properties. Particular emphasis is placed on quantitative shape analysis based on 3D scanning, point cloud analysis, and x-ray microtomography. Despite substantial volumetric as well as anisotropic deformation, we demonstrate repeatability of the printed construct and its properties.
Stochastic oscillations and dragon king avalanches in self-organized quasi-critical systems
Authors: Kinouchi Osame , Brochini Ludmila , Costa Ariadne A. , Campos João Guilherme Ferreira , Copelli Mauro
Published: March 2019

In the last decade, several models with network adaptive mechanisms (link deletion-creation, dynamic synapses, dynamic gains) have been proposed as examples of self-organized criticality (SOC) to explain neuronal avalanches. However, all these systems present stochastic oscillations hovering around the critical region that are incompatible with standard SOC. Here we make a linear stability analysis of the mean field fixed points of two self-organized quasi-critical systems: a fully connected network of discrete time stochastic spiking neurons with firing rate adaptation produced by dynamic neuronal gains and an excitable cellular automata with depressing synapses. We find that the fixed point corresponds to a stable focus that loses stability at criticality. We argue that when this focus is close to become indifferent, demographic noise can elicit stochastic oscillations that frequently fall into the absorbing state. This mechanism interrupts the oscillations, producing both power law avalanches and dragon king events, which appear as bands of synchronized firings in raster plots. Our approach differs from standard SOC models in that it predicts the coexistence of these different types of neuronal activity.
Increasing the frequency of peripheral component in paired associative stimulation strengthens its efficacy
Authors: Tolmacheva Aleksandra , Mäkelä Jyrki P. , Shulga Anastasia
Published: March 2019

Paired associative stimulation (PAS), a combination of transcranial magnetic stimulation (TMS) with peripheral nerve stimulation (PNS), is emerging as a promising tool for alleviation of motor deficits in neurological disorders. The effectiveness and feasibility of PAS protocols are essential for their use in clinical practice. Plasticity induction by conventional PAS can be variable and unstable. Protocols effective in challenging clinical conditions are needed. We have shown previously that PAS employing 50 Hz PNS enhances motor performance in chronic spinal cord injury patients and induces robust motor-evoked potential (MEP) potentiation in healthy subjects. Here we investigated whether the effectiveness of PAS can be further enhanced. Potentiation of MEPs up to 60 minutes after PAS with PNS frequencies of 25, 50, and 100 Hz was tested in healthy subjects. PAS with 100 Hz PNS was more effective than 50 (P = 0.009) and 25 Hz (P = 0.016) protocols. Moreover, when administered for 3 days, PAS with 100 Hz led to significant MEP potentiation on the 3rd day (P = 0.043) even when the TMS target was selected suboptimally (modelling cases where finding an optimal site for TMS is problematic due to a neurological disease). PAS with 100 Hz PNS is thus effective and feasible for clinical applications.
Phenology, mobility and behaviour of the arcto-alpine species Boloria napaea in its arctic habitat
Authors: Ehl Stefan , Holzhauer Stephanie I. J. , Ryrholm Nils , Schmitt Thomas
Published: March 2019

Arctic and alpine environments present extreme, but different, challenges to survival. We therefore studied the ecological adaptation of the arctic-alpine fritillary Boloria napaea in northern Sweden and compared these results with the eastern Alps. Using mark-release-recapture, we analysed phenology, mobility, activity patterns, change in wing condition and nectar sources. The phenology showed no protandry, but a longer flight period of the females. Wing conditions revealed a linear decay being quicker in males than females. The mean flight distances were higher for males than females (143 vs 92 m). In general, males were more flight active, while females invested more time in feeding and resting. The shortness of the flight period in the Arctic is apparently a particular adaptation to these harsh conditions, not even allowing protandry, and constraining all individuals to hatch during a short period. These conditions also forced the individuals to concentrate on flight and alimentation. In general, Arctic and Alpine populations of B. napaea show few differences, but the species seems to be even better adapted to the northern environments. Thus, the short temporal separation of these populations seems not to have been sufficient for a divergent adaptation in the southern mountains.
Rotatable precipitates change the scale-free to scale dependent statistics in compressed Ti nano-pillars
Authors: Pan Yan , Wu Haijun , Wang Xiaofei , Sun Qiaoyan , Xiao Lin , Ding Xiangdong , Sun Jun , Salje Ekhard K. H.
Published: March 2019

Compressed nano-pillars crackle from moving dislocations, which reduces plastic stability. Crackling noise is characterized by stress drops or strain bursts, which scale over a large region of sizes leading to power law statistics. Here we report that this “classic” behaviour is not valid in Ti-based nanopillars for a counterintuitive reason: we tailor precipitates inside the nano-pillar, which “regulate” the flux of dislocations. It is not because the nano-pillars become too small to sustain large dislocation movements, the effect is hence independent of size. Our precipitates act as “rotors”: local stress initiates the rotation of inclusions, which reduces the stress amplitudes dramatically. The size distribution of stress drops simultaneously changes from power law to exponential. Rotors act like revolving doors limiting the number of passing dislocations. Hence each collapse becomes weak. We present experimental evidence for Ti-based nano-pillars (diameters between 300 nm and 2 μm) with power law distributions of crackling noise P(s) ∼ s−τ with τ ∼ 2 in the defect free or non-rotatable precipitate states. Rotors change the size distribution to P(s) ∼ exp(−s/s0). Rotors are inclusions of ω-phase that aligns under stress along slip planes and limit dislocation glide to small distances with high nucleation rates. This opens new ways to make nano-pillars more stable.
A novel graphene barrier against moisture by multiple stacking large-grain graphene
Authors: Gomasang Ploybussara , Kawahara Kenji , Yasuraoka Kenta , Maruyama Mina , Ago Hiroki , Okada Susumu , Ueno Kazuyoshi
Published: March 2019

The moisture barrier properties of stacked graphene layers on Cu surfaces were investigated with the goal of improving the moisture barrier efficiency of single-layer graphene (SLG) for Cu metallization. SLG with large grain size were stacked on Cu surfaces coated with CVD-SLG to cover the grain-boundaries and defective areas of the underneath SLG film, which was confirmed to be oxidized by Raman spectroscopy measurements. To evaluate the humidity resistance of the graphene-coated Cu surfaces, temperature humidity storage (THS) testing was conducted under accelerated oxidation conditions (85 °C and 85% relative humidity) for 100 h. The color changes of the Cu surfaces during THS testing were observed by optical microscopy, while the oxidized Cu into Cu2O and CuO was detected by X-ray photoelectron spectroscopy (XPS). The experimental results were accord with the results of first-principle simulation for the energetic barrier against water diffusion through the stacked graphene layers with different overlap. The results demonstrate the efficiency of SLG stacking approach against moisture for Cu metallization.
Long term results of down-staging and liver transplantation for patients with hepatocellular carcinoma beyond the conventional criteria
Authors: Ravaioli Matteo , Odaldi Federica , Cucchetti Alessandro , Trevisani Franco , Piscaglia Fabio , De Pace Vanessa , Bertuzzo Valentina Rosa , Neri Flavia , Golfieri Rita , Cappelli Alberta , D’Errico Antonietta , Cescon Matteo , Del Gaudio Massimo , Fallani Guido , Siniscalchi Antonio , Morelli Maria Cristina , Ciccarese Francesca , Di Marco Maria , Farinati Fabio , Giannini Edoardo Giovanni , Pinna Antonio Daniele
Published: March 2019

The objective of the study is to evaluate 10 years of down-staging strategy for liver transplantation (LT) with a median follow-up of 5 years. Data on long-term results are poor and less information is available for hepatocellular carcinoma (HCC) non-responder patients or those ineligible for down-staging. The outcome of 308 HCC candidates and the long-term results of 231 LTs for HCC performed between 2003 and 2013 were analyzed. HCCs were divided according to tumor stage and response to therapy: 145 patients were T2 (metering Milan Criteria, MC), 43 were T3 successfully down-staged to T2 (Down-Achieved), 20 were T3 not fully down-staged to T2 (Down-not Achieved), and 23 patients were T3 not receiving down-staging treatments (No-Down). The average treatment effect (ATE) of LT for T3 tumors was estimated using the outcome of 535 T3 patients undergoing non-LT therapies, using inverse probability weighting regression adjustment. The 24-month drop-out rate during waiting time was significantly higher in the down-staging groups: 27.6% vs. 9.2%, p < 0.005. After LT, the tumor recurrence rate was significantly different: MC 7.6%, Down-Achieved 20.9%, Down-not Achieved 31.6%, and No-Down 30.4% (p < 0.001). The survival rates at 5 years were: 63% in Down-Achieved, 62% in Down-not Achieved, 63% in No-Down, and 77% in MC (p = n.s.). The only variable related to a better outcome was the effective down-staging to T2 at the histological evaluation of the explanted liver: recurrence rate = 7.8% vs. 26% (p < 0.001) and 5-year patient survival = 76% vs. 67% (p < 0.05). The ATE estimation showed that the mean survival of T3-LT candidates was significantly better than that of T3 patients ineligible for LT [83.3 vs 39.2 months (+44.6 months); p < 0.001]. Long term outcome of T3 down-staged candidates was poorer than that of MC candidates, particularly for cases not achieving down-staging. However, their survival outcome was significantly better than that achieved with non-transplant therapies.
Structure-function relationship of a citrus salicylate methylesterase and role of salicylic acid in citrus canker resistance
Authors: Lima Silva Caio Cesar de , Shimo Hugo Massayoshi , de Felício Rafael , Mercaldi Gustavo Fernando , Rocco Silvana Aparecida , Benedetti Celso Eduardo
Published: March 2019

Salicylic acid (SA) and its methyl ester, methyl salicylate (MeSA) are well known inducers of local and systemic plant defense responses, respectively. MeSA is a major mediator of systemic acquired resistance (SAR) and its conversion back into SA is thought to be required for SAR. In many plant species, conversion of MeSA into SA is mediated by MeSA esterases of the SABP2 family. Here we show that the Citrus sinensis SABP2 homologue protein CsMES1 catalyzes the hydrolysis of MeSA into SA. Molecular modeling studies suggest that CsMES1 shares the same structure and SA-binding mode with tobacco SABP2. However, an amino acid polymorphism in the active site of CsMES1-related proteins suggested an important role in enzyme regulation. We present evidence that the side chain of this polymorphic residue directly influences enzyme activity and SA binding affinity in CsMES proteins. We also show that SA and CsMES1 transcripts preferentially accumulate during the incompatible interaction between Xanthomonas aurantifolii pathotype C and sweet orange plants. Moreover, we demonstrate that SA and MeSA inhibited citrus canker caused by Xanthomonas citri, whereas an inhibitor of CsMES1 enhanced canker formation, suggesting that CsMES1 and SA play a role in the local defense against citrus canker bacteria.
Application of a Flow-Based Hollow-Fiber Co-Culture System to Study Cellular Influences under Hyperglycemic Conditions
Authors: Ebrahim Abdul Shukkur , Carion Thomas W. , Strand Eliisa , Young Laura A. , Shi Haoshen , Berger Elizabeth A.
Published: March 2019

Elucidation of the basic mechanisms underlying human disease pathogenesis depends on the findings afforded to us through in vivo and in vitro approaches. While there are inherent limitations in any model system, 2D in vitro culture systems tend to be particularly restricted due to their static nature. Here, we adapted a flow-based hollow-fiber cartridge system to better understand the cellular influences of human retinal microvascular endothelial cells and mouse-derived neutrophils under high glucose conditions similar to those observed in diabetes. Analyses by western blot and flow cytometry indicate that pro-inflammatory molecules known to be associated with the pathogenesis of diabetic retinopathy were significantly elevated following high glucose exposure, including VEGF, ICAM-1, and ROS. Changes in mitochondrial potential were also observed. Further, we demonstrate that this innovative system allows for cross-species co-culture as well as long-term culturing conditions. This in vitro modeling system not only mimics the retinal microvasculature, it also allows for the examination of cellular interactions and mechanisms that contribute to diabetic retinopathy, a visually debilitating complication of diabetes.
Development of a novel short 12-meric papiliocin-derived peptide that is effective against Gram-negative sepsis
Authors: Kim Jieun , Jacob Binu , Jang Mihee , Kwak Chulhee , Lee Yeongjoon , Son Kkabi , Lee Sujin , Jung In Duk , Jeong Myeong Seon , Kwon Seung-Hae , Kim Yangmee
Published: March 2019

The development of novel peptide antibiotics with potent activity against multidrug-resistant Gram-negative bacteria and anti-septic activity is urgently needed. In this study, we designed short, 12-meric antimicrobial peptides by substituting amino acids from the N-terminal 12 residues of the papiliocin (Pap12-1) peptide to alter cationicity and amphipathicity and improve antibacterial activity and bacterial membrane interactions. Pap12-6, with an amphipathic α-helical structure and Trp12 at the C-terminus, showed broad-spectrum antibacterial activity, especially against multidrug-resistant Gram-negative bacteria. Dye leakage, membrane depolarization, and electron microscopy data proved that Pap12-6 kills bacteria by permeabilizing the bacterial membrane. Additionally, Pap12-6 significantly reduced the secretion of NO, TNF-α, and IL-6 and secreted alkaline phosphatase reporter gene activity confirmed that Pap12-6 shows anti-inflammatory activity via a TLR4-mediated NF-κB signaling pathway. In a mouse sepsis model, Pap12-6 significantly improved survival, reduced bacterial growth in organs, and reduced LPS and inflammatory cytokine levels in the serum and organs. Pap12-6 showed minimal cytotoxicity towards mammalian cells and controlled liver and kidney damage, proving its high bacterial selectivity. Our results suggest that Pap12-6 is a promising peptide antibiotic for the therapeutic treatment of Gram-negative sepsis via dual bactericidal and immunomodulatory effects on the host.
Long-term Use of Clozapine is Protective for Bone Density in Patients with Schizophrenia
Authors: Lin Chieh-Hsin , Lin Chun-Yuan , Wang Hong-Song , Lane Hsien-Yuan
Published: March 2019

Low bone mineral density (BMD) prevails among patients with schizophrenia. Antipsychotics use plays an important role in BMD. Previous cross-section study suggests that clozapine treatment may benefit BMD of women with schizophrenia. However, the effect of long-term clozapine therapy on BMD remains unknown. This prospective study compared clozapine and non-clozapine antipsychotics in long-term effects on BMD among both men and women with schizophrenia. Patients with schizophrenia and age-matched healthy individuals were enrolled from two centers. All patients, including clozapine receivers and non-clozapine antipsychotics recipients, kept clinically stable with unchanged antipsychotics and doses for at least 6 months at enrollment and during the follow-up period. BMD was examined by dual-energy X-ray absorptiometer upon enrollment and at 1- or 3-year follow-up. Thorough clinical and laboratory variables were measured too. The mean BMD of patients receiving clozapine was higher than that of the non-clozapine patients at both enrollment and follow-up. Overall, the patients in the clozapine group gained BMD, while those in the non-clozapine group lost BMD after 1–3 years (p = 0.015). There was no significant difference of BMD change between clozapine-treated patients and healthy controls. Factors associated with BMD change in the clozapine group included calcium level (B = −0.607, p = 0.021) and T3 level (B = −0.077, p = 0.007). This longitudinal study suggests that long-term clozapine treatment may protect BMD compared to prolactin-raising and non-clozapine prolactin-sparing antipsychotics among patients with schizophrenia. Future prospective studies are warranted to testify whether switching from non-clozapine antipsychotics to clozapine can rescue BMD.
Research on the Hong-Ou-Mandel interference with two independent sources
Authors: Wang Si , Liu Chen-Xi , Li Jian , Wang Qin
Published: March 2019

In this paper, we carry out investigation on the HOM interference between two independent photons by using interference filters with different bandwidth both in theory and experiment. Our experimental results are consistent with the theoretical predictions. From the experimental and theoretical results, we find that interference filters with a narrower bandwidth can help to give a larger coherence length, due to the broadening of photon wave-packet in the spatial domain, resulting in an higher interference visibility. Furthermore, a combination of interference filters with different bandwidths may help to achieve a nice balance between coincidence counting rate and interference visibility. Our present work might provide valuable reference for further implementation of HOM interference in the field of quantum information.
Soil carbon is a useful surrogate for conservation planning in developing nations
Authors: Peri Pablo L. , Lasagno Romina G. , Martínez Pastur Guillermo , Atkinson Rachel , Thomas Evert , Ladd Brenton
Published: March 2019

Defining the optimal placement of areas for biodiversity conservation in developing nations remains a significant challenge. Our best methods for spatially targeting potential locations for biodiversity conservation rely heavily on extensive georeferenced species observation data which is often incomplete or lacking in developing nations. One possible solution is the use of surrogates that enable site assessments of potential biodiversity values which use either indicator taxa or abiotic variables, or both. Among the plethora of abiotic variables, soil carbon has previously been identified as a potentially powerful predictor for threatened biodiversity, but this has not yet been confirmed with direct observational data. Here we assess the potential value of soil carbon for spatial prediction of threatened species using direct measurements as well as a wide range of GIS derived abiotic values as surrogates for threatened plant species in the PEBANPA network of permanent plots in Southern Patagonia. We find that soil carbon significantly improves the performance of a biodiversity surrogate elaborated using abiotic variables to predict the presence of threatened species. Soil carbon could thus help to prioritize sites in conservation planning. Further, the results suggest that soil carbon on its own can be a much better surrogate than other abiotic variables when prioritization of sites for conservation are calibrated on increasingly small sets of observation plots. We call for the inclusion of soil carbon data in the elaboration of surrogates used to optimize conservation investments in the developing world.
Ultra compact electrochemical metallization cells offering reproducible atomic scale memristive switching
Authors: Cheng Bojun , Emboras Alexandros , Salamin Yannick , Ducry Fabian , Ma Ping , Fedoryshyn Yuriy , Andermatt Samuel , Luisier Mathieu , Leuthold Juerg
Published: March 2019

Here we show electrochemical metallization cells with compact dimensions, excellent electrical performance, and reproducible characteristics. An advanced technology platform has been developed to obtain Ag/SiO2/Pt devices with ultra-scaled footprints (15 × 15 nm2), inter-electrode distances down to 1 nm, and a transition from the OFF to ON resistance state relying on the relocation of only few atoms. This technology permits a well-controlled metallic filament formation in a highly confined field at the apex of an atomic scale tip. As a consequence of this miniaturization process, we achieve set voltages around 100 mV, ultra-fast switching times of 7.5 ns, and write energies of 18 fJ. Furthermore, we demonstrate very good cell-to-cell uniformity and a resistance extinction ratio as high as 6 · 105. Combined ab-initio quantum transport simulations and experiments suggest that the manufactured structures exhibit reduced self-heating effects due to their lower dimensions, making them very promising candidates as next-generation (non-)volatile memory components.