bluuebunny/crossref_metadata_2025 huggingface dataset:
Needs Assessment for Simulation Training for Prehospital Providers in Botswana
Authors: Glomb Nicolaus W. , Kosoko Adeola A. , Doughty Cara B. , Rus Marideth C. , Shah Manish I. , Cox Megan , Galapi Cafen , Parkes Presley S. , Kumar Shelley , Laba Bushe
Published: November 2018

Background

In June 2012, the Botswana Ministry of Health and Wellness (MOHW; Gaborone, Botswana) initiated a national Emergency Medical Services (EMS) system in response to significant morbidity and mortality associated with prehospital emergencies. The MOHW requested external expertise to train its developing workforce. Simulation-based training was planned to equip these health care providers with clinical knowledge, procedural skills, and communication techniques.

Objective

The objective of this study was to assess the educational needs of the pioneer Botswana MOHW EMS providers based on retrospective EMS logbook review and EMS provider feedback to guide development of a novel educational curriculum.

Methods

Data were abstracted from a representative sample of the Gaborone, Botswana MOHW EMS response log from 2013-2014 and were quantified into the five most common call types for both adults and children. Informal focus groups with health professionals and EMS staff, as well as surveys, were used to rank common response call types and self-perceived educational needs.

Results

Based on 1,506 calls, the most common adult response calls were for obstetric emergencies, altered mental status, gastrointestinal/abdominal pain, trauma, gynecological emergencies, and cardiovascular and respiratory distress-related emergencies. The most common pediatric response calls were for respiratory distress, gastrointestinal complaints/dehydration, trauma and musculoskeletal injuries, newborn delivery, seizures, and toxic ingestion/exposure. The EMS providers identified these same chief complaints as priorities for training using the qualitative approach. A locally relevant, simulation-based curriculum for the Botswana MOHW EMS system was developed and implemented based on these data.

Conclusions

: Trauma, respiratory distress, gastrointestinal complaints, and puerperal/perinatal emergencies were common conditions for all age groups. Other age-specific conditions were also identified as educational needs based on epidemiologic data and provider feedback. This needs assessment may be useful when designing locally relevant EMS curricula in other low-income and middle-income countries.GlombNW, KosokoAA, DoughtyCB, RusMC, ShahMI, CoxM, GalapiC, ParkesPS, KumarS, LabaB.Needs assessment for simulation training for prehospital providers in Botswana. Prehosp Disaster Med. 2018;33(6):621–626.
Ambivalence About Forgiveness
Authors: Fricker Miranda
Published: November 2018

Our ideas about forgiveness seem to oscillate between idealization and scepticism. How should we make sense of this apparent conflict? This paper argues that we should learn something from each, seeing these views as representing opposing moments in a perennial and well-grounded moral ambivalence towards forgiveness. Once we are correctly positioned, we shall see an aspect of forgiveness that recommends precisely this ambivalence. For what will come into view will be certain key psychological mechanisms of moral-epistemic influence – other-addressed and self-addressed mechanisms of moral social construction – that enable forgiveness to function well when it is well-functioning, but which are also intrinsically prone to deterioration into one or another form of bad faith. Thus forgiveness is revealed as necessarily containing seeds of its own corruption, showing ambivalence to be a generically appropriate attitude. Moreover, it is emphasized that where forgiver and forgiven are relating to one another in the context of asymmetries of social power, the practice of forgiveness is likely to be further compromised, notably increasing the risk of negative influence on the moral-epistemic states of either the forgiver or the forgiven, or both.
Analogy-driven change: the emergence and development of mirativeend upconstructions in American English
Authors: SERRANO-LOSADA MARIO
Published: November 2018

This article explores the diachronic development of mirativeend upin American English, which emerged in the late nineteenth century and which seems to be, at present, in the process of becoming a parenthetical element. The rise of the various mirativeend upconstructions is argued to be the result of both pragmatic enrichment and paradigmatic analogy, motivated by a series of semantically and formally related expressions, most prominently by mirativeturn out. Moreover, the article delves into the process of cooptation to explain the emergence of parenthetical instances in the present-day language. Cooptation is understood as an intrinsically analogical-driven mechanism when it entails the eventual grammaticalization of formulaic parenthetical constructions. Data for the present study were taken from a variety of diachronic and synchronic sources, which include COHA, COCA and NOW, among others.
SPECTRAL ANALYSIS OF MORSE–SMALE FLOWS I: CONSTRUCTION OF THE ANISOTROPIC SPACES
Authors: Dang Nguyen Viet , Rivière Gabriel
Published: November 2018

We prove the existence of a discrete correlation spectrum for Morse–Smale flows acting on smooth forms on a compact manifold. This is done by constructing spaces of currents with anisotropic Sobolev regularity on which the Lie derivative has a discrete spectrum.
Creation and delivery of a complex 3D geological survey for the Glasgow area and its application to urban geology
Authors: Kearsey T. I. , Whitbread K. , Arkley S. L. B. , Finlayson A. , Monaghan A. A. , McLean W. S. , Terrington R. L. , Callaghan E. A. , Millward D. , Campbell S. D. G.
Published: November 2018

The Glasgow area has a combination of highly variable superficial deposits and a legacy of heavy industry, quarrying and mining. These factors create complex foundation and hydrological conditions, influencing the movement of contaminants through the subsurface and giving rise locally to unstable ground conditions. Digital geological three-dimensional models developed by the British Geological Survey are helping to resolve the complex geology underlying Glasgow, providing a key tool for planning and environmental management. The models, covering an area of 3200km2to a depth of 1.2km, include glacial and post-glacial deposits and the underlying, faulted Carboniferous igneous and sedimentary rocks. Control data, including 95,000 boreholes, digital mine plans and published geological maps, were used in model development. Digital outputs from the models include maps of depth to key horizons, such as rockhead or depth to mine workings. The models have formed the basis for the development of site-scale high-resolution geological models and provide input data for a wide range of other applications from groundwater modelling to stochastic lithological modelling.
Asymmetric Cooling of the Atlantic and Pacific Arctic During the Past Two Millennia: A Dual Observation‐Modeling Study
Authors: Zhong Y. , Jahn A. , Miller G. H. , Geirsdottir A.
Published: November 2018

The past 2,000 years provide a critical context for understanding twentieth century climate change. Due to the Past Global Changes 2k initiative, an extensive proxy database provides opportunities to assess regional climate change that have stronger ecological and societal implications than global‐mean temperature changes alone. However, the various sources of paleoclimate reconstruction poses serious challenges to scientifically and statistically sound inference within a unified framework. Here we show results from the first transient simulation for the past 2,000 years with the Community Earth System Model, called past2k, and use data‐model comparison to refine the interpretation of the proxy data. Our results indicate that the Atlantic Arctic was cooling at a faster rate than the Pacific Arctic over the past two millennia, in both proxy data and models. The model shows that this cooling pattern was dynamically supported by both a weakening of North Atlantic subpolar gyre and a stronger Aleutian Low.
Ribosomal protein S27-like regulates autophagy via the β-TrCP-DEPTOR-mTORC1 axis
Authors: Xiong Xiufang , Liu Xia , Li Haomin , He Hengqian , Sun Yi , Zhao Yongchao
Published: November 2018

RPS27L (Ribosomal protein S27-like), an evolutionarily conserved ribosomal protein, is a p53 target and a physiological p53 regulator. We previously reported that Rps27l disruption enhanced lymphomagenesis in Trp53+/− mice by triggering genome instability and sensitized Trp53+/− mice to radiation by blocking DNA damage response. Whether and how RPS27L modulates autophagy is totally unknown. Here we report that RPS27L silencing significantly induced autophagy in breast cancer MB231 and SK-BR3 cells harboring mutant p53. Mechanistically, RPS27L silencing remarkably inactivated mTORC1, a major negative autophagy regulator, but not mTORC2. Autophagy induction and mTORC1 inactivation was also observed in MEFs with Rps27l deletion. More specifically, RPS27L silencing shortened the protein half-life of β-TrCP, a substrate receptor of Skp1-Cullin 1-F-box (SCF) ubiquitin ligase, which is responsible for DEPTOR degradation, leading to DEPTOR accumulation to inhibit mTORC1 activity. Furthermore, RPS27L silencing-induced autophagy and mTORC1 inactivation can be partially rescued by simultaneous DEPTOR silencing, suggesting a causal role of DEPTOR. Biologically, autophagy inhibitor, chloroquine (CQ), or Bafilomycin A1 (BAF A1), significantly induced apoptosis in RPS27L silenced cells, indicating that autophagy is a cellular survival mechanism in response to RPS27L loss. Finally, RPS27L levels were reduced in human breast cancers, as compared to adjacent normal tissues. Collectively, our study suggests that RPS27L reduction might play a promoting role during breast tumorigenesis by autophagy induction via the β-TrCP-DEPTOR-mTORC1 axis.
Nitric oxide triggers the assembly of “type II” stress granules linked to decreased cell viability
Authors: Aulas Anaïs , Lyons Shawn M. , Fay Marta M. , Anderson Paul , Ivanov Pavel
Published: November 2018

We show that 3-morpholinosydnonimine (SIN-1)-induced nitric oxide (NO) triggers the formation of SGs. Whereas the composition of NO-induced SGs is initially similar to sodium arsenite (SA)-induced type I (cytoprotective) SGs, the progressive loss of eIF3 over time converts them into pro-death (type II) SGs. NO-induced SG assembly requires the phosphorylation of eIF2α, but the transition to type II SGs is temporally linked to the mTOR-regulated displacement of eIF4F complexes from the m7 guanine cap. Whereas SA does not affect mitochondrial morphology or function, NO alters mitochondrial integrity and function, resulting in increased ROS production, decreased cytoplasmic ATP, and plasma membrane permeabilization, all of which are supported by type II SG assembly. Thus, cellular energy balance is linked to the composition and function of NO-induced SGs in ways that determine whether cells live or die.
Continuous negative-to-positive tuning of thermal expansion achieved by controlled gas sorption in porous coordination frameworks
Authors: Auckett Josie E. , Barkhordarian Arnold A. , Ogilvie Stephen H. , Duyker Samuel G. , Chevreau Hubert , Peterson Vanessa K. , Kepert Cameron J.
Published: November 2018

Control of the thermomechanical properties of functional materials is of great fundamental and technological significance, with the achievement of zero or negative thermal expansion behavior being a key goal for various applications. A dynamic, reversible mode of control is demonstrated for the first time in two Prussian blue derivative frameworks whose coefficients of thermal expansion are tuned continuously from negative to positive values by varying the concentration of adsorbed CO2. A simple empirical model that captures site-specific guest contributions to the framework expansion is derived, and displays excellent agreement with the observed lattice behaviour.
Intellectual synthesis in mentorship determines success in academic careers
Authors: Liénard Jean F. , Achakulvisut Titipat , Acuna Daniel E. , David Stephen V.
Published: November 2018

As academic careers become more competitive, junior scientists need to understand the value that mentorship brings to their success in academia. Previous research has found that, unsurprisingly, successful mentors tend to train successful students. But what characteristics of this relationship predict success, and how? We analyzed an open-access database of 18,856 researchers who have undergone both graduate and postdoctoral training, compiled across several fields of biomedical science with an emphasis on neuroscience. Our results show that postdoctoral mentors were more instrumental to trainees’ success compared to graduate mentors. Trainees’ success in academia was also predicted by the degree of intellectual synthesis between their graduate and postdoctoral mentors. Researchers were more likely to succeed if they trained under mentors with disparate expertise and integrated that expertise into their own work. This pattern has held up over at least 40 years, despite fluctuations in the number of students and availability of independent research positions.
Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy
Authors: Gayi Elinam , Neff Laurence A. , Massana Muñoz Xènia , Ismail Hesham M. , Sierra Marta , Mercier Thomas , Décosterd Laurent A. , Laporte Jocelyn , Cowling Belinda S. , Dorchies Olivier M. , Scapozza Leonardo
Published: November 2018

X-linked myotubular myopathy (XLMTM, also known as XLCNM) is a severe congenital muscular disorder due to mutations in the myotubularin gene, MTM1. It is characterized by generalized hypotonia, leading to neonatal death of most patients. No specific treatment exists. Here, we show that tamoxifen, a well-known drug used against breast cancer, rescues the phenotype of Mtm1-deficient mice. Tamoxifen increases lifespan several-fold while improving overall motor function and preventing disease progression including lower limb paralysis. Tamoxifen corrects functional, histological and molecular hallmarks of XLMTM, with improved force output, myonuclei positioning, myofibrillar structure, triad number, and excitation-contraction coupling. Tamoxifen normalizes the expression level of the XLMTM disease modifiers DNM2 and PI3KC2B, likely contributing to the phenotypic rescue. Our findings demonstrate that tamoxifen is a promising candidate for clinical evaluation in XLMTM patients.
Palladium concave nanocrystals with high-index facets accelerate ascorbate oxidation in cancer treatment
Authors: Chong Yu , Dai Xing , Fang Ge , Wu Renfei , Zhao Lin , Ma Xiaochuan , Tian Xin , Lee Sangyun , Zhang Chao , Chen Chunying , Chai Zhifang , Ge Cuicui , Zhou Ruhong
Published: November 2018

Intravenous pharmacological dose of ascorbate has been proposed as a potential antitumor therapy; however, its therapeutic efficacy is limited due to the slow autoxidation. Here, we report that palladium (Pd) nanocrystals, which possess intrinsic oxidase-like activity, accelerate the autoxidation of ascorbate, leading to the enhancement of its antitumor efficacy. The oxidase-like activity of Pd nanocrystals was facet-dependent, with the concave nanostructure enclosed by high-index facets catalyzing ascorbate autoxidation more efficiently than the planar nanostructure enclosed by low-index facets. Our first-principles calculations provide the underlying molecular mechanisms for the facet-dependent activation of O2 molecule and subsequent ascorbate oxidation. Further in vitro and in vivo assays demonstrate the enhancement of the antitumor efficacy of ascorbate with these Pd concave nanocubes. Our animal experiments also indicate the combined approach with both ascorbate and Pd concave nanocubes displays an even better efficacy than currently available clinical medicines, with no obvious cytotoxicity to normal cells.
Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells
Authors: Lund Harald , Pieber Melanie , Parsa Roham , Han Jinming , Grommisch David , Ewing Ewoud , Kular Lara , Needhamsen Maria , Espinosa Alexander , Nilsson Emma , Överby Anna K. , Butovsky Oleg , Jagodic Maja , Zhang Xing-Mei , Harris Robert A.
Published: November 2018

Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1CreER/+R26DTA/+ mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1+F4/80lowClec12a– microglia and infiltration of CX3CR1+F4/80hiClec12a+ macrophages that arise directly from Ly6Chi monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6Chi monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct.
Invasive Salmonella exploits divergent immune evasion strategies in infected and bystander dendritic cell subsets
Authors: Aulicino Anna , Rue-Albrecht Kevin C. , Preciado-Llanes Lorena , Napolitani Giorgio , Ashley Neil , Cribbs Adam , Koth Jana , Lagerholm B. Christoffer , Ambrose Tim , Gordon Melita A. , Sims David , Simmons Alison
Published: November 2018

Non-typhoidalSalmonella(NTS) are highly prevalent food-borne pathogens. Recently, a highly invasive, multi-drug resistantS. Typhimurium, ST313, emerged as a major cause of bacteraemia in children and immunosuppressed adults, however the pathogenic mechanisms remain unclear. Here, we utilize invasive and non-invasiveSalmonellastrains combined with single-cell RNA-sequencing to study the transcriptome of individual infected and bystander monocyte-derived dendritic cells (MoDCs) implicated in disseminating invasive ST313. Compared with non-invasiveSalmonella, ST313 directs a highly heterogeneous innate immune response. Bystander MoDCs exhibit a hyper-activated profile potentially diverting adaptive immunity away from infected cells. MoDCs harbouring invasiveSalmonelladisplay higher expression ofIL10andMARCH1concomitant with lower expression ofCD83to evade adaptive immune detection. Finally, we demonstrate how these mechanisms conjointly restrain MoDC-mediated activation ofSalmonella-specific CD4+T cell clones. Here, we show how invasive ST313 exploits discrete evasion strategies within infected and bystander MoDCs to mediate its dissemination in vivo.
Manipulation of the dephasing time by strong coupling between localized and propagating surface plasmon modes
Authors: Yang Jinghuan , Sun Quan , Ueno Kosei , Shi Xu , Oshikiri Tomoya , Misawa Hiroaki , Gong Qihuang
Published: November 2018

Strong coupling between two resonance modes leads to the formation of new hybrid modes exhibiting disparate characteristics owing to the reversible exchange of information between different uncoupled modes. Here, we realize the strong coupling between the localized surface plasmon resonance and surface plasmon polariton Bloch wave using multilayer nanostructures. An anticrossing behavior with a splitting energy of 144 meV can be observed from the far-field spectra. More importantly, we investigate the near-field properties in both the frequency and time domains using photoemission electron microscopy. In the frequency domain, the near-field spectra visually demonstrate normal-mode splitting and display the extent of coupling. Importantly, the variation of the dephasing time of the hybrid modes against the detuning is observed directly in the time domain. These findings signify the evolution of the dissipation and the exchange of information in plasmonic strong coupling systems and pave the way to manipulate the dephasing time of plasmon modes, which can benefit many applications of plasmonics.
Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a-subtype macrophage activation in obesity
Authors: Kubota Tetsuya , Inoue Mariko , Kubota Naoto , Takamoto Iseki , Mineyama Tomoka , Iwayama Kaito , Tokuyama Kumpei , Moroi Masao , Ueki Kohjiro , Yamauchi Toshimasa , Kadowaki Takashi
Published: November 2018

M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood. Herein, we demonstrate that, the IL-4/Irs2/Akt pathway is selectively impaired, along with decreased macrophage Irs2 expression, although IL-4/STAT6 pathway is maintained. Indeed, myeloid cell-specific Irs2-deficient mice show impairment of IL-4-induced M2a-subtype macrophage activation, as a result of stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex, resulting in insulin resistance under the HF diet condition. Moreover, the reduction of macrophage Irs2 expression is mediated by hyperinsulinemia via the insulin receptor (IR). In myeloid cell-specific IR-deficient mice, the IL-4/Irs2 pathway is preserved in the macrophages, which results in a reduced degree of insulin resistance, because of the lack of IR-mediated downregulation of Irs2. We conclude that downregulation of Irs2 in macrophages caused by hyperinsulinemia is responsible for systemic insulin resistance via impairment of M2a-subtype macrophage activation in obesity.
Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis
Authors: Saavedra Pedro H. V. , Huang Linyan , Ghazavi Farzaneh , Kourula Stephanie , Vanden Berghe Tom , Takahashi Nozomi , Vandenabeele Peter , Lamkanfi Mohamed
Published: November 2018

Clostridium difficile is the leading cause of pseudomembranous colitis in hospitalized patients. C. difficile enterotoxins TcdA and TcdB promote this inflammatory condition via a cytotoxic response on intestinal epithelial cells (IECs), but the underlying mechanisms are incompletely understood. Additionally, TcdA and TcdB engage the Pyrin inflammasome in macrophages, but whether Pyrin modulates CDI pathophysiology is unknown. Here we show that the Pyrin inflammasome is not functional in IECs and that Pyrin signaling is dispensable for CDI-associated IEC death and for in vivo pathogenesis. Instead, our studies establish that C. difficile enterotoxins induce activation of executioner caspases 3/7 via the intrinsic apoptosis pathway, and demonstrate that caspase-3/7-mediated IEC apoptosis is critical for in vivo host defense during early stages of CDI. In conclusion, our findings dismiss a critical role for inflammasomes in CDI pathogenesis, and identify IEC apoptosis as a host defense mechanism that restricts C. difficile infection in vivo.
The 27 kDa Trypanosoma brucei Pentatricopeptide Repeat Protein is a G-tract Specific RNA Binding Protein
Authors: Kamba Pakoyo F. , Dickson David A. , White Neil A. , Ekstrom Jennifer L. , Koslowsky Donna J. , Hoogstraten Charles G.
Published: November 2018

Pentatricopeptide repeat (PPR) proteins, a helical repeat family of organellar RNA binding proteins, play essential roles in post-transcriptional RNA processing. In Trypanosoma brucei, an expanded family of PPR proteins localize to the parasite’s single mitochondrion, where they are believed to perform important roles in both RNA processing and translation. We studied the RNA binding specificity of the simplest T. brucei PPR protein (KRIPP11) using electrophoretic mobility shift assays, fluorescence anisotropy, circular dichroism spectroscopy, and in vitro selection. We found KRIPP11 to be an RNA binding protein with specificity for sequences of four or more consecutive guanosine residues (G-tracts). Such G-tracts are dramatically enriched in T. brucei mitochondrial transcripts that are destined for extensive uridine insertion/deletion editing but are not present in mRNAs following editing. We further found that the quadruplex oligoguanosine RNA conformation is preferentially recognized by KRIPP11 over other conformational forms, and is bound without disruption of the quadruplex structure. In combination with prior data demonstrating association of KRIPP11 with the small ribosomal subunit, these results suggest possible roles for KRIPP11 in bridging mRNA maturation and translation or in facilitating translation of unusual dual-coded open reading frames.
Electrophysiological properties of human beta-cell lines EndoC-βH1 and -βH2 conform with human beta-cells
Authors: Hastoy Benoît , Godazgar Mahdieh , Clark Anne , Nylander Vibe , Spiliotis Ioannis , van de Bunt Martijn , Chibalina Margarita V. , Barrett Amy , Burrows Carla , Tarasov Andrei I. , Scharfmann Raphael , Gloyn Anna L. , Rorsman Patrik
Published: November 2018

Limited access to human islets has prompted the development of human beta cell models. The human beta cell lines EndoC-βH1 and EndoC-βH2 are increasingly used by the research community. However, little is known of their electrophysiological and secretory properties. Here, we monitored parameters that constitute the glucose-triggering pathway of insulin release. Both cell lines respond to glucose (6 and 20 mM) with 2- to 3-fold stimulation of insulin secretion which correlated with an elevation of [Ca2+]i, membrane depolarisation and increased action potential firing. Similar to human primary beta cells, KATP channel activity is low at 1 mM glucose and is further reduced upon increasing glucose concentration; an effect that was mimicked by the KATP channel blocker tolbutamide. The upstroke of the action potentials reflects the activation of Ca2+ channels with some small contribution of TTX-sensitive Na+ channels. The repolarisation involves activation of voltage-gated Kv2.2 channels and large-conductance Ca2+-activated K+ channels. Exocytosis presented a similar kinetics to human primary beta cells. The ultrastructure of these cells shows insulin vesicles composed of an electron-dense core surrounded by a thin clear halo. We conclude that the EndoC-βH1 and -βH2 cells share many features of primary human β-cells and thus represent a useful experimental model.
Microfluidic Assay Measures Increased Neutrophil Extracellular Traps Circulating in Blood after Burn Injuries
Authors: Otawara Masayuki , Roushan Maedeh , Wang Xiao , Ellett Felix , Yu Yong-Ming , Irimia Daniel
Published: November 2018

Cell-free DNA (cf-DNA) concentration in human plasma is often increased after burn and trauma injuries. Two major sources of cf-DNA are the parenchymal cells damaged by the injury and various circulating cells indirectly altered by the response to injury. The cf-DNA originating from neutrophils, also known as circulating neutrophil extracellular traps (cNETs), is of notable interest because cNETs have been associated with pathological processes in other conditions, including cancer, autoimmunity, etc. Both intact chromatin and oligonucleotides, which are the by-product of cf-DNA degradation, are assumed to contribute to the cf-DNA in patients. However, traditional assays for cf-DNA quantification do not distinguish between cNETs and cf-DNA of other origins and do not differentiate between intact chromatin and oligonucleotides. Here we measure the amount of intact cNETs in the circulation, using a microfluidic device that mechanically traps chromatin fibers directly from blood and an immunofluorescence protocol that detects neutrophil-specific proteins associated with chromatin. In a rat model of burn injury, we determined that the chromatin fibers in the circulation after injury originate exclusively from neutrophils and are cNETs. We found that the concentration of cNETs surges the first day after injury and then decreases slowly over several days. In a secondary sepsis model, which involved a burn injury followed by cecal-ligation-puncture, we measured additional increases in cNETs in the days after sepsis was induced. These results validate a microfluidic assay for the quantification of cNETs and will facilitate fruther studies probing the contribution of cNETs to complications after burns and sepsis.
Trends and regional variations in the administrative prevalence of attention-deficit/hyperactivity disorder among children and adolescents in Germany
Authors: Akmatov M. K. , Steffen A. , Holstiege J. , Hering R. , Schulz M. , Bätzing J.
Published: November 2018

There is a controversy regarding temporal trends in prevalence of attention-deficit/hyperactivity disorder (ADHD). Using nationwide claims data containing data for approximately six million statutory health insured children we aimed to examine a) trends of ADHD administrative prevalence during 2009–2016; b) regional variations in prevalence, and c) factors associated with an increased chance of ADHD diagnosis. The ICD-10 code ‘F90-hyperkinetic disorder’ was used to define an ADHD case. Global and Local Moran’s I tests were used to examine the spatial autocorrelation and k-means-cluster analysis to examine the course of ADHD prevalence in administrative districts over years. Two-level logistic regression was applied to examine individual- and district-level factors associated with ADHD diagnosis. The administrative prevalence of ADHD was 4.33% (95% CI: 4.31–4.34%). We observed pronounced small-area differences on the district level with prevalences ranging between 1.6% and 9.7%. There was evidence of strong spatial autocorrelation (Global Moran’s I: 0.46, p < 0.0001). The k-means-method identified six clusters of different size; all with a stagnating trend in the prevalence over the observation period of eight years. On the district level, a lower proportion of foreign citizens, and a higher density of paediatric psychiatrists and paediatricians were positively associated with ADHD with a more pronounced effect in urban districts.
An altered gene expression profile in tyramine-exposed intestinal cell cultures supports the genotoxicity of this biogenic amine at dietary concentrations
Authors: del Rio Beatriz , Redruello Begoña , Ladero Victor , Cal Santiago , Obaya Alvaro J. , Alvarez Miguel A.
Published: November 2018

Tyramine, histamine and putrescine are the most commonly detected and most abundant biogenic amines (BA) in food. The consumption of food with high concentrations of these BA is discouraged by the main food safety agencies, but legal limits have only been set for histamine. The present work reports a transcriptomic investigation of the oncogenic potential of the above-mentioned BA, as assessed in the HT29 human intestinal epithelial cell line. Tyramine had a greater effect on the expression of genes involved in tumorigenesis than did histamine or putrescine. Since some of the genes that showed altered expression in tyramine-exposed cells are involved in DNA damage and repair, the effect of this BA on the expression of other genes involved in the DNA damage response was investigated. The results suggest that tyramine might be genotoxic for intestinal cells at concentrations easily found in BA-rich food. Moreover, a role in promoting intestinal cancer cannot be excluded.
Taxon-specific responses to different forestry treatments in a temperate forest
Authors: Elek Zoltán , Kovács Bence , Aszalós Réka , Boros Gergely , Samu Ferenc , Tinya Flóra , Ódor Péter
Published: November 2018

There are only few studies that explore the ecological consequences of forest management on several organism groups. We studied the short-term effects of four forestry treatments including preparation cutting, clear-cutting, retention tree group and gap-cutting in a temperate managed forest on the assemblage structure of understory plants, enchytraeid worms, spiders and ground beetles. Here we show, that the effect of treatments on the different facets of assemblage structure was taxon-specific. Clear-cutting and retention tree group strongly impoverished enchytraeids assemblages. Even if the species richness and cover of plants increased in clear-cutting and gap-cutting, their species composition moderately changed after treatments. For spiders only their species composition was influenced by the treatments, while the response of ground beetles was slightly affected. Short-term effect of forest management interventions on biodiversity might be compensated by the dispersal (spiders, ground beetles) and resilience (plants) of organism groups, however sedentary soil organism showed high sensitivity.
Atypical postural control can be detected via computer vision analysis in toddlers with autism spectrum disorder
Authors: Dawson Geraldine , Campbell Kathleen , Hashemi Jordan , Lippmann Steven J. , Smith Valerie , Carpenter Kimberly , Egger Helen , Espinosa Steven , Vermeer Saritha , Baker Jeffrey , Sapiro Guillermo
Published: November 2018

Evidence suggests that differences in motor function are an early feature of autism spectrum disorder (ASD). One aspect of motor ability that develops during childhood is postural control, reflected in the ability to maintain a steady head and body position without excessive sway. Observational studies have documented differences in postural control in older children with ASD. The present study used computer vision analysis to assess midline head postural control, as reflected in the rate of spontaneous head movements during states of active attention, in 104 toddlers between 16–31 months of age (Mean = 22 months), 22 of whom were diagnosed with ASD. Time-series data revealed robust group differences in the rate of head movements while the toddlers watched movies depicting social and nonsocial stimuli. Toddlers with ASD exhibited a significantly higher rate of head movement as compared to non-ASD toddlers, suggesting difficulties in maintaining midline position of the head while engaging attentional systems. The use of digital phenotyping approaches, such as computer vision analysis, to quantify variation in early motor behaviors will allow for more precise, objective, and quantitative characterization of early motor signatures and potentially provide new automated methods for early autism risk identification.
Fluoride-doped amorphous calcium phosphate nanoparticles as a promising biomimetic material for dental remineralization
Authors: Iafisco Michele , Degli Esposti Lorenzo , Ramírez-Rodríguez Gloria Belén , Carella Francesca , Gómez-Morales Jaime , Ionescu Andrei Cristian , Brambilla Eugenio , Tampieri Anna , Delgado-López José Manuel
Published: November 2018

Demineralization of dental hard tissue is a widespread problem and the main responsible for dental caries and dentin hypersensitivity. The most promising strategies to induce the precipitation of new mineral phase are the application of materials releasing gradually Ca2+ and PO43− ions or mimicking the mineral phase of the host tissue. However, the design of formulations covering both processes is so far a challenge in preventive dentistry. In this work, we have synthesized innovative biomimetic amorphous calcium phosphate (ACP), which has been, for the first time, doped with fluoride ions (FACP) to obtain materials with enhanced anti-caries and remineralizing properties. Significantly, the doping with fluoride (F) did not vary the physico-chemical features of ACP but resulted in a faster conversion to the crystalline apatite phase in water, as observed by in-situ time-dependent Raman experiments. The efficacy of the as synthesized ACP and FACP samples to occlude dentinal tubules and induce enamel remineralization has been tested in vitro in human molar teeth. The samples showed good ability to partially occlude the tubules of acid-etched dentin and to restore demineralized enamel into its native structure. Results demonstrate that ACP and FACP are promising biomimetic materials in preventive dentistry to hinder demineralization of dental hard tissues.
Deep transfer learning-based hologram classification for molecular diagnostics
Authors: Kim Sung-Jin , Wang Chuangqi , Zhao Bing , Im Hyungsoon , Min Jouha , Choi Hee June , Tadros Joseph , Choi Nu Ri , Castro Cesar M. , Weissleder Ralph , Lee Hakho , Lee Kwonmoo
Published: November 2018

Lens-free digital in-line holography (LDIH) is a promising microscopic tool that overcomes several drawbacks (e.g., limited field of view) of traditional lens-based microcopy. However, extensive computation is required to reconstruct object images from the complex diffraction patterns produced by LDIH. This limits LDIH utility for point-of-care applications, particularly in resource limited settings. We describe a deep transfer learning (DTL) based approach to process LDIH images in the context of cellular analyses. Specifically, we captured holograms of cells labeled with molecular-specific microbeads and trained neural networks to classify these holograms without reconstruction. Using raw holograms as input, the trained networks were able to classify individual cells according to the number of cell-bound microbeads. The DTL-based approach including a VGG19 pretrained network showed robust performance with experimental data. Combined with the developed DTL approach, LDIH could be realized as a low-cost, portable tool for point-of-care diagnostics.
Bioavailability of a novel form of silicon supplement
Authors: Scholey D. V. , Belton D. J. , Burton E. J. , Perry C. C.
Published: November 2018

In this study, we assessed uptake and potential efficacy of a novel, pH neutral form of silicon supplement in vitro and using broiler chickens as a model species. In vitro bioavailability of this supplement was significantly higher than other commercial supplements tested, all of which claim available silica content. To confirm bioavailability of the new supplement in vivo, a broiler chick feeding trial reported blood uptake that was significantly higher than a Bamboo-derived silicon supplement. We assessed dose response of the novel supplement in a further study with increased dose related levels of silicon being detected in the blood and tibia. We found tibia and foot ash residue as a percentage of dry mass was higher with inclusion of the novel supplement in the diet, particularly in young birds and that this was followed by significant increase in tibia breaking strength. This novel supplement may therefore have applications in the improvement of bone integrity, with implications for the reduction of lameness in broilers. These results indicate the novel silica supplement is readily absorbed in chicks, and transported in the blood supply to sites such as the skeleton due to it being present in a non-condensed, monomeric form. There is potential for wider application of this silica supplement in other species where bone breakages are a problem, including high performance sport.
Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes
Authors: Guo Lili , Wang Qingqing , Weng Liwei , Hauser Lauren A. , Strawser Cassandra J. , Mesaros Clementina , Lynch David R. , Blair Ian A.
Published: November 2018

Frataxin is a highly conserved protein encoded by the frataxin (FXN) gene. The full-length 210-amino acid form of protein frataxin (1–210; isoform A) expressed in the cytosol of cells rapidly translocates to the mitochondria, where it is converted to the mature form (81–210) by mitochondrial processing peptidase. Mature frataxin (81–210) is a critically important protein because it facilitates the assembly of mitochondrial iron-sulfur cluster protein complexes such as aconitase, lipoate synthase, and succinate dehydrogenases. Decreased expression of frataxin protein is responsible for the devastating rare genetic disease of Friedreich’s ataxia. The mitochondrial form of frataxin has long been thought to be present in erythrocytes even though paradoxically, erythrocytes lack mitochondria. We have discovered that erythrocyte frataxin is in fact a novel isoform of frataxin (isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times as much isoform E in erythrocytes (20.9 ± 6.4 ng/mL) from the whole blood of healthy volunteers (n = 10) when compared with the mature mitochondrial frataxin present in other blood cells (7.1 ± 1.0 ng/mL). Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich’s ataxia and monitor the efficacy of therapeutic interventions.
Campylobacter jejuni bile exposure influences outer membrane vesicles protein content and bacterial interaction with epithelial cells
Authors: Taheri Nayyer , Mahmud A. K. M. Firoj , Sandblad Linda , Fällman Maria , Wai Sun Nyunt , Fahlgren Anna
Published: November 2018

Campylobacter jejuni is a prevalent human pathogen and a major cause of bacterial gastroenteritis in the world. In humans, C. jejuni colonizes the intestinal tract and its tolerance to bile is crucial for bacteria to survive and establish infection. C. jejuni produces outer membrane vesicles (OMVs) which have been suggested to be involved in virulence. In this study, the proteome composition of C. jejuni OMVs in response to low concentration of bile was investigated. We showed that exposure of C. jejuni to low concentrations of bile, similar to the concentration in cecum, induced significant changes in the protein profile of OMVs released during growth without affecting the protein profile of the bacteria. This suggests that bile influences a selective packing of the OMVs after bacterial exposure to low bile. A low concentration of bile was found to increase bacterial adhesion to intestinal epithelial cells, likely by an enhanced hydrophobicity of the cell membrane following exposure to bile. The increased bacterial adhesiveness was not associated with increased invasion, instead bile exposure decreased C. jejuni invasion. OMVs released from bacteria upon exposure to low bile showed to increase both adhesion and invasion of non-bile-exposed bacteria into intestinal epithelial cells. These findings suggest that C. jejuni in environments with low concentrations of bile produce OMVs that facilitates colonization of the bacteria, and this could potentially contribute to virulence of C. jejuni in the gut.
IL-1β- and IL-4-polarized macrophages have opposite effects on adipogenesis of intramuscular fibro-adipogenic progenitors in humans
Authors: Moratal C. , Raffort J. , Arrighi N. , Rekima S. , Schaub S. , Dechesne C. A. , Chinetti G. , Dani C.
Published: November 2018

Intramuscular fat deposition represents a negative prognostic factor for several myopathies, metabolic diseases and aging. Fibro-adipogenic progenitors (FAPs) are considered as the main source of intramuscular adipocytes, but the mechanisms controlling their adipogenic potential are still not elucidated in humans. The aim of this study was to explore the regulation of human FAP adipogenesis by macrophages. We found that CD140a-expressing FAPs were located close to CD68 positive macrophages in muscles from patients with Duchenne muscular dystrophy (DMD). This strongly suggests a potential interaction between FAPs and macrophages in vivo. Isolated human primary FAPs were then differentiated in the presence of conditioned media obtained from primary blood monocyte-polarized macrophages. Molecules released by IL-1β-polarized macrophages (M(IL-1β)) drastically reduced FAP adipogenic potential as assessed by decreased cellular lipid accumulation and reduced gene expression of adipogenic markers. This was associated with an increased gene expression of pro-inflammatory cytokines in FAPs. Conversely, factors secreted by IL-4-polarized macrophages (M(IL-4)) enhanced FAP adipogenesis. Finally, the inhibition of FAP adipocyte differentiation by M(IL-1β) macrophages requires the stimulation of Smad2 phosphorylation of FAPs. Our findings identify a novel potential crosstalk between FAPs and M(IL-1β) and M(IL-4) macrophages in the development of adipocyte accumulation in human skeletal muscles.
Coexistence of turbulence-like and glassy behaviours in a photonic system
Authors: González Iván R. R. , Raposo Ernesto P. , Macêdo Antônio M. S. , de S. Menezes Leonardo , Gomes Anderson S. L.
Published: November 2018

Coexistence of physical phenomena can occur in quite unexpected ways. Here we demonstrate the first evidence in any physical system of the coexistence in the same set of measurements of two of the most challenging phenomena in complex systems: turbulence and spin glasses. We employ a quasi-one-dimensional random fibre laser, which displays all essential ingredients underlying both behaviours, namely disorder, frustration and nonlinearity, as well as turbulent energy cascades and intermittent energy flux between fluctuation scales. Our extensive experimental results are theoretically supported by a newly defined photonic Pearson correlation coefficient that unveils the role of the intermittency and describes remarkably well both the spin-glass Parisi overlap parameter and the distribution of turbulent-like intensity increments. Our findings open the way to unravel subtle connections with other complex phenomena, such as disordered nonlinear wave propagation, Lévy statistics of intensity fluctuations, and rogue waves.
Phase contrast time-lapse microscopy datasets with automated and manual cell tracking annotations
Authors: Ker Dai Fei Elmer , Eom Sungeun , Sanami Sho , Bise Ryoma , Pascale Corinne , Yin Zhaozheng , Huh Seung-il , Osuna-Highley Elvira , Junkers Silvina N. , Helfrich Casey J. , Liang Peter Yongwen , Pan Jiyan , Jeong Soojin , Kang Steven S. , Liu Jinyu , Nicholson Ritchie , Sandbothe Michael F. , Van Phu T. , Liu Anan , Chen Mei , Kanade Takeo , Weiss Lee E. , Campbell Phil G.
Published: November 2018

Phase contrast time-lapse microscopy is a non-destructive technique that generates large volumes of image-based information to quantify the behaviour of individual cells or cell populations. To guide the development of algorithms for computer-aided cell tracking and analysis, 48 time-lapse image sequences, each spanning approximately 3.5 days, were generated with accompanying ground truths for C2C12 myoblast cells cultured under 4 different media conditions, including with fibroblast growth factor 2 (FGF2), bone morphogenetic protein 2 (BMP2), FGF2 + BMP2, and control (no growth factor). The ground truths generated contain information for tracking at least 3 parent cells and their descendants within these datasets and were validated using a two-tier system of manual curation. This comprehensive, validated dataset will be useful in advancing the development of computer-aided cell tracking algorithms and function as a benchmark, providing an invaluable opportunity to deepen our understanding of individual and population-based cell dynamics for biomedical research.