bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of follow-up in transition to adult CHD: a single-centre experience
Authors: Kollengode Madhukar S. , Daniels Curt J. , Zaidi Ali N.
Published: July 2018

Lapses in care during transition in adult CHD patients lead to increased morbidity and mortality. Previous studies have investigated predictors of poor follow-up in universal healthcare paradigms and select American populations. We studied patients with a wide spectrum of CHD severity within a single American centre to identify factors associated with successful internal transition and maintenance of care. Loss of follow-up was defined as no documented cardiac follow-up for ⩾3 years. Ambulatory cardiology patients aged 16–17 years with CHD were retrospectively enrolled and contacted. A survey assessing demographics, patients’ understanding of their CHD, medical status, and barriers to care was administered. On the basis of chart review of 197 enrolled patients, 74 demonstrated loss of follow-up (37.6%). Of 78 successfully contacted patients, 58 were surveyed, of whom a minority had loss of follow-up (n=16). The status of most patients with loss of follow-up was not known. Maintenance of care was associated with greater complexity of CHD (p<0.01), establishment of care with an adult CHD provider (p<0.001), use of prescription medications (p<0.001), and receipt of education emphasising the importance of long-term cardiac care (p<0.003). Insurance lapses were not associated with loss of follow-up (p=0.08). Transition and maintenance of care was suboptimal even within a single centre. Over one-third of patients did not maintain care. Patients with greater-complexity CHD, need for medications, receipt of transition education, and care provided by adult CHD providers had superior follow-up.
Merging Undergraduate Teaching, Graduate Training, and Producing Research: Lessons from Three Collaborative Experiments
Authors: Bolsen Toby W. , Fairbanks Bailey R. , Aviles Eduardo E. , Pritchett Reagan G. , Kingsland Justin T. , LaPlant Kristina M. , Montgomery Matthew D. , Rogol Natalie C.
Published: July 2018

Teaching undergraduate students, mentoring graduate students, and generating publishable research are distinct tasks for many political scientists. This article highlights lessons for merging these activities through experiences from an initiative that sparked a series of collaborative-research projects focused on opinions about crime and punishment in the United States. This article describes three collaborative projects conducted between 2015 and 2017 to demonstrate how to merge undergraduate teaching, graduate training, and producing research. By participating in these projects, students learned about social-scientific research through hands-on experiences designing experiments, collecting and analyzing original data, and reporting empirical findings to a public audience. This approach is an effective way to engage students and generate research that can advance professional goals.
What is a Social Practice?
Authors: Haslanger Sally
Published: July 2018

This paper provides an account of social practices that reveals how they are constitutive of social agency, enable coordination around things of value, and are a site for social intervention. The social world, on this account, does not begin when psychologically sophisticated individuals interact to share knowledge or make plans. Instead, culture shapes agents to interpret and respond both to each other and the physical world around us. Practices shape us as we shape them. This provides resources for understanding why social practices tend to be stable, but also reveals sites and opportunities for change. (Challenge social meanings! Intervene in the material conditions!)
Lady Parts: The Metaphysics of Pregnancy
Authors: Kingma Elselijn
Published: July 2018

What is the metaphysical relationship between the fetus/embryo and the pregnant organism? In this paper I apply a substance metaphysics view developed by Barry Smith and Berit Brogaard to argue, on the basis of topological connectedness, that fetuses/embryos are Lady-Parts: part of the maternal organism up until birth. This leaves two options. Either mammalian organisms begin at birth, or we revise our conception of organisms such that mammalian organisms can be part of other mammals. The first option has some advantages: it is numerically neat; aligns with an intuitive picture of organisms as physically distinct individuals; and ties ‘coming into existence’ to a suitably recognisable and important event: birth. But it denies that the fetus survives birth, or that human organisms existed prior to their birth. The second option allows us to recognise that human organisms exist prior to and survive their birth, but at a cost: it leaves the question of when an organism comes into existence unanswered, and demands potentially far-reaching conceptual revision across a range of domains.
Towards a Hylomorphic Solution to the Grounding Problem
Authors: Koslicki Kathrin
Published: July 2018

Concrete particular objects (e.g. living organisms) figure saliently in our everyday experience as well as our in our scientific theorizing about the world. Ahylomorphicanalysis of concrete particular objects holds that these entities are, in some sense, compounds of matter (hūlē) and form (morphēoreidos). TheGrounding Problemasks why an object and its matter (e.g. a statue and the clay that constitutes it) can apparently differ with respect to certain of their properties (e.g. the clay's ability to survive being squashed, as compared to the statue's inability to do so), even though they are otherwise so much alike. In this paper, I argue that a hylomorphic analysis of concrete particular objects, in conjunction with a non-modal conception of essence of the type encountered for example in the works of Aristotle and Kit Fine, has the resources to yield a solution to the Grounding Problem.
Essence and Mere Necessity
Authors: Leech Jessica
Published: July 2018

Recently, a debate has developed between those who claim that essence can be explained in terms ofde remodality (modalists), and those who claim thatde remodality can be explained in terms of essence (essentialists). The aim of this paper is to suggest that we should reassess. It is assumed that either necessity is to be accounted for in terms of essence, or that essence is to be accounted for in terms of necessity. I will argue that we should assume neither. I discuss what role these key notions – essence and necessity – can reasonably be thought to contribute to our understanding of the world, and argue that, given these roles, there is no good reason to think that we should give an account of one in terms of the other. I conclude: if we can adequately explainde remodality and essence at all, we should aim to do so separately.
Cardinals, Ordinals, and the Prospects for a Fregean Foundation
Authors: Snyder Eric , Shapiro Stewart , Samuels Richard
Published: July 2018

There are multiple formal characterizations of the natural numbers available. Despite being inter-derivable, they plausibly codify different possible applications of the naturals – doing basic arithmetic, counting, and ordering – as well as different philosophical conceptions of those numbers: structuralist, cardinal, and ordinal. Some influential philosophers of mathematics have argued for a non-egalitarian attitude according to which one of those characterizations is ‘more basic’ or ‘more fundamental’ than the others. This paper addresses two related issues. First, we review some of these non-egalitarian arguments, lay out a laundry list of different, legitimate, notions of relative priority, and suggest that these arguments plausibly employ different such notions. Secondly, we argue that given a metaphysical-cum-epistemological gloss suggested by Frege's foundationalist epistemology, the ordinals are plausibly more basic than the cardinals. This is just one orientation to relative priority one could take, however. Ultimately, we subscribe to an egalitarian attitude towards these formal characterizations: they are, in some sense, equally ‘legitimate’.
Near‐Real‐Time Assimilation of SAR‐Derived Flood Maps for Improving Flood Forecasts
Authors: Hostache Renaud , Chini Marco , Giustarini Laura , Neal Jeffrey , Kavetski Dmitri , Wood Melissa , Corato Giovanni , Pelich Ramona‐Maria , Matgen Patrick
Published: July 2018

Short‐ to medium‐range flood forecasts are central to predicting and mitigating the impact of flooding across the world. However, producing reliable forecasts and reducing forecast uncertainties remains challenging, especially in poorly gauged river basins. The growing availability of synthetic aperture radar (SAR)‐derived flood image databases (e.g., generated from SAR sensors such as Envisat advanced synthetic aperture radar) provides opportunities to improve flood forecast quality. This study contributes to the development of more accurate global and near real‐time remote sensing‐based flood forecasting services to support flood management. We take advantage of recent algorithms for efficient and automatic delineation of flood extent using SAR images and demonstrate that near real‐time sequential assimilation of SAR‐derived flood extents can substantially improve flood forecasts. A case study based on four flood events of the River Severn (United Kingdom) is presented. The forecasting system comprises the SUPERFLEX hydrological model and the Lisflood‐FP hydraulic model. SAR images are assimilated using a particle filter. To quantify observation uncertainty as part of data assimilation, we use an image processing approach that assigns each pixel a probability of being flooded based on its backscatter values. Empirical results show that the sequential assimilation of SAR‐derived flood extent maps leads to a substantial improvement in water level forecasts. Forecast errors are reduced by as much as 50% at the assimilation time step, and improvements persist over subsequent time steps for 24 to 48 hr. The proposed approach holds promise for improving flood forecasts at locations where observed data availability is limited but satellite coverage exists.
Dark and Stormy: How More Rainfall Leads to Warm and Murky Lakes
Authors: Cook Terri
Published: July 2018

Reduced clarity in two northeastern Pennsylvania lakes has resulted in warmer surface water and cooler bottom water despite stable regional air temperatures during the past 3 decades.
Toward Standardized Data Sets for Climate Model Experimentation
Authors: Durack Paul , Taylor Karl , Eyring Veronika , Ames Sasha , Hoang Tony , Nadeau Denis , Doutriaux Charles , Stockhause Martina , Gleckler Peter
Published: July 2018

A new initiative collects, archives, and documents climate forcing data sets to support coordinated modeling activities that study past, present, and future climates.
Quantifying Compressible Groundwater Storage by Combining Cross‐Hole Seismic Surveys and Head Response to Atmospheric Tides
Authors: Rau Gabriel C. , Acworth R. Ian , Halloran Landon J. S. , Timms Wendy A. , Cuthbert Mark O.
Published: July 2018

Groundwater specific storage varies by orders of magnitude, is difficult to quantify, and prone to significant uncertainty. Estimating specific storage using aquifer testing is hampered by the nonuniqueness in the inversion of head data and the assumptions of the underlying conceptual model. We revisit confined poroelastic theory and reveal that the uniaxial specific storage can be calculated mainly from undrained poroelastic properties, namely, uniaxial bulk modulus, loading efficiency, and the Biot‐Willis coefficient. In addition, literature estimates of the solid grain compressibility enables quantification of subsurface poroelastic parameters using field techniques such as cross‐hole seismic surveys and loading efficiency from the groundwater responses to atmospheric tides. We quantify and compare specific storage depth profiles for two field sites, one with deep aeolian sands and another with smectitic clays. Our new results require bulk density and agree well when compared to previous approaches that rely on porosity estimates. While water in clays responds to stress, detailed sediment characterization from a core illustrates that the majority of water is adsorbed onto minerals leaving only a small fraction free to drain. This, in conjunction with a thorough analysis using our new method, demonstrates that specific storage has a physical upper limit of
 m−1. Consequently, if larger values are derived using aquifer hydraulic testing, then the conceptual model that has been used needs reappraisal. Our method can be used to improve confined groundwater storage estimates and refine the conceptual models used to interpret hydraulic aquifer tests.
Predicting Global Ground Geoelectric Field With Coupled Geospace and Three‐Dimensional Geomagnetic Induction Models
Authors: Honkonen I. , Kuvshinov A. , Rastätter L. , Pulkkinen A.
Published: July 2018

We forecast the global effects of space weather on the geoelectric and geomagnetic fields using a novel combination of methods. We use a realistic three‐dimensional (3‐D) model of Earth's electrical conductivity and a realistic representation of magnetospheric and ionospheric current systems. Our scheme involves the following steps: (1) We run a global magnetohydrodynamic model of the magnetosphere coupled to an electrostatic model of the ionosphere. (2) We calculate a global time series of the ground magnetic field resulting from the ionospheric, field‐aligned, and magnetospheric currents of the global magnetohydrodynamic model. (3) We approximate this external field by an equivalent source current flowing in a thin shell above Earth. (4) We calculate a global time series of geoelectric and geomagnetic fields from the equivalent current and a 3‐D conductivity model of Earth that also takes into account the coast effect due to large horizontal conductivity gradient. We verify our implementation by comparing the results against known analytic and numeric solutions, and then apply our scheme to the geomagnetic storm of 14 and 15 December 2006. In particular, we show that accounting for 3‐D structure of Earth's conductivity results in significantly enhanced geoelectric field at large lateral gradients of conductivity, especially in coastal regions, both at middle and high latitudes. In the studied geomagnetic storm the largest values of 3‐D geoelectric field are detected at high latitudes reaching 2.5 V/km and the 3‐D effect extends inland by a few hundred kilometers.
Statistics of Durations and Spacings of Equatorial Plasma Depletions Detected by the C/NOFS Planar Langmuir Probe
Authors: Costa Emanoel , Roddy Patrick A. , Ballenthin John O. , Groves Keith M.
Published: July 2018

The Planar Langmuir Probe onboard the Communication/Navigation Outage Forecasting System satellite monitored ionospheric plasma densities and their irregularities with high resolution almost seamlessly for approximately five years since May 2008. Planar Langmuir Probe data from two different years (1 October 2008 to 30 September 2009 and 5 June 2012 to 4 June 2013) were selected for analysis. The first data set corresponds to solar minimum conditions, and the second one is as close to solar maximum conditions of solar cycle 24 as possible, with basis on their continuous availability. The results from a level‐crossing analysis applied to detrended evening‐time data from a fixed altitude range show how depletion durations and spacings between consecutive depletions are statistically distributed as functions of solar activity and longitude sector. In quantitative terms, they show that (i) the fewer depletions observed in the solar‐minimum year are also shorter, shallower, and closer together than those detected in the more active one and (ii) great similarities exist between structures of depletion durations and spacings between consecutive depletions observed in the South American and African longitude sectors, which are more noticeable than those associated with in the Indian‐Asian longitude sector.
Non-Invasive Markers (ALBI and APRI) Predict Pregnancy Outcomes in Women With Chronic Liver Disease
Authors: Gonsalkorala Enoka S. , Cannon Mary D. , Lim Tiong Yeng , Penna Leonie , Willliamson Catherine , Heneghan Michael A.
Published: July 2018

objectives:

Rates of pregnancy in women with cirrhosis are increasing. Risk of hepatic decompensation during pregnancy, therefore, merits tailored obstetric and hepatology care. Prognostic markers that determine pregnancy outcomes are lacking.

METHODS:

Medical records of women who attended hepatology clinic at King’s College Hospital with chronic liver disease (CLD) who became pregnant from 1983 to 2017 were reviewed. Information on demographics, clinical history, serology, and outcome of pregnancy was collected.

RESULTS:

In all, 165 pregnancies occurred in 100 women with CLD including 80 pregnancies in 48 women with cirrhosis. Median age of conception in cirrhotic and non-cirrhotic women were 26 years (16–44) and 28 years (16–51) respectively (p = 0.015). Whilst women with cirrhosis had similar live birth rate to non-cirrhotic women (75 vs. 85% p = 0.119), they were significantly less likely to proceed beyond 37 weeks gestation (45 vs. 58% p = 0.033). Women who received preconception counseling were more likely to have stable liver disease at conception (100 vs 86% p = 0.02). Compared with preconception MELD (model for end stage liver disease), preconception Albumin-Bilirubin score (ALBI) more accurately predicted live birth with an area under the receiver-operator curve (AUROC) of 0.741 (p < 0.001), and preconception AST to platelet ratio index (APRI) more accurately predicted ability to proceed beyond 37 weeks gestation with an AUROC of 0.700 (p < 0.001).

CONCLUSIONS:

Most women with cirrhosis who conceived achieved a successful pregnancy outcome. ALBI and APRI scores can prognosticate pregnancy outcomes in women with CLD. Preconception counseling by a hepatologist or specialist obstetrician improved patient care in this group.
Imbalanced LIMK1 and LIMK2 expression leads to human colorectal cancer progression and metastasis via promoting β-catenin nuclear translocation
Authors: Zhang Yue , Li Aimin , Shi Jiaolong , Fang Yuxin , Gu Chuncai , Cai Jianqun , Lin Chuang , Zhao Liang , Liu Side
Published: July 2018

Epithelial–mesenchymal transition (EMT)-induced metastasis contributes to human colorectal cancer (CRC) progression, especially in advanced CRC. However, the underlying mechanism of β-catenin in this process is elusive. We identified that LIM domain kinase (LIMK)2 was progressively downregulated with tumor progression from precancerous lesions to advanced cancer. Gain- and loss-of-function assays revealed that LIMK2 inhibits cell proliferation via cell cycle arrest at the G1–S transition and suppresses the ability of cell metastasis by restricting the EMT process. Reduced LIMK2 expression enhanced the nuclear accumulation of β-catenin and activated the Wnt signaling pathway, thus contributing to tumor progression. A homolog of the LIMK family, LIMK1, which was overexpressed throughout tumor progression, served as a competitive inhibitor of LIMK2 via β-catenin nuclear translocation. The imbalanced expression of LIMK1 and LIMK2 is important in CRC progression, and the combined effects provide a new insight into the mechanism of CRC progression. These findings provide a new understanding for LIMK-based anticancer therapy.
Knockdown of Yin Yang 1 enhances anticancer effects of cisplatin through protein phosphatase 2A-mediated T308 dephosphorylation of AKT
Authors: Zhao Lu , Li Ran , Gan Ye-Hua
Published: July 2018

Cisplatin is still one of the first-line drugs for chemotherapy of head and neck squamous cell carcinoma (HNSCC) and shows a survival advantage for HNSCC. However, a substantial proportion of HNSCC eventually becomes resistance to cisplatin and the underlying mechanisms remain to be fully understood. Yin Yang 1 (YY1) is a multifunctional protein regulating both gene transcription and protein modifications and also plays a role in chemotherapy resistance. Here, we reported that knockdown of YY1 by lentivirus-mediated short hairpin RNA or tetracycline-inducible short hairpin RNA enhanced cisplatin-induced apoptosis and inhibition of cell proliferation, migration and invasion in the HNSCC cell lines, and inhibition of the xenograft tumor growth. The underlying mechanisms were revealed that knockdown of YY1 downregulated both S473 and T308 phosphorylation of AKT (protein kinase B), which was mainly responsible for cisplatin resistance, whereas overexpression of YY1 upregulated both S473 and T308 phosphorylation. Cisplatin upregulated YY1 mRNA and protein expression and both S473 and T308 phosphorylation of AKT. In the presence of cisplatin, knockdown of YY1 not only blocked cisplatin-induced increase in S473 and T308 phosphorylation of AKT, but still downregulated T308 phosphorylation. Moreover, protein phosphatase 2A (PP2A) antagonist, okadaic acid, upregulated T308, but not S473, phosphorylation, and simultaneously abolished YY1 knockdown-mediated enhancement of cisplatin-induced inhibition of cell proliferation. In addition, knockdown of YY1 promoted PP2A activity through upregulating mRNA and protein expressions of PP2A catalytic subunit alpha (PPP2CA) through the binding of YY1 in the promoter of PPP2CA. Conversely, activating PP2A by forskolin also promoted YY1 degradation and subsequently inhibited T308 phosphorylation. These results suggested that knockdown of YY1 enhanced anticancer effects of cisplatin through PP2A mediating T308 dephosphorylation of AKT, and that targeting YY1 or PP2A would enhance the efficiency of cisplatin chemotherapy in treatment of HNSCC.
FOXP3 inhibits angiogenesis by downregulating VEGF in breast cancer
Authors: Li Xiaoju , Gao Yuan , Li Jialin , Zhang Kuo , Han Jun , Li Weina , Hao Qiang , Zhang Wangqian , Wang Shuning , Zeng Cheng , Zhang Wei , Zhang Yingqi , Li Meng , Zhang Cun
Published: July 2018

Forkhead box P3 (FOXP3), an X-linked tumor suppressor gene, plays an important role in breast cancer. However, the biological functions of FOXP3 in breast cancer angiogenesis remain unclear. Here we found that the clinical expression of nuclear FOXP3 was inversely correlated with breast cancer angiogenesis. Moreover, the animal study demonstrated that FOXP3 significantly reduced the microvascular density of MDA-MB-231 tumors transplanted in mice. The cytological experiments showed that the supernatant from FOXP3-overexpressing cells exhibited a diminished ability to stimulate tube formation and sprouting in HUVECs in vitro. In addition, expression of vascular endothelial growth factor (VEGF) was downregulated by FOXP3 in breast cancer cell lines. Luciferase reporter assays and chromatin immunoprecipitation assays demonstrated that FOXP3 can directly interact with the VEGF promoter via specific forkhead-binding motifs to suppress its transcription. Importantly, the inhibitory effects of FOXP3 in the supernatant on tube formation and sprouting in HUVECs could be reversed by adding VEGF in vitro. Nuclear FOXP3 expression was inversely correlated with VEGF expression in clinical breast cancer tissues, and FOXP3 downregulation and VEGF upregulation were both correlated with reduced survival in breast cancer data sets in the Kaplan–Meier plotter. Taken together, our data demonstrate that FOXP3 suppresses breast cancer angiogenesis by downregulating VEGF expression.
AAV vector-mediated in vivo reprogramming into pluripotency
Authors: Senís Elena , Mosteiro Lluc , Wilkening Stefan , Wiedtke Ellen , Nowrouzi Ali , Afzal Saira , Fronza Raffaele , Landerer Henrik , Abad Maria , Niopek Dominik , Schmidt Manfred , Serrano Manuel , Grimm Dirk
Published: July 2018

In vivo reprogramming of somatic cells into induced pluripotent stem cells (iPSC) holds vast potential for basic research and regenerative medicine. However, it remains hampered by a need for vectors to express reprogramming factors (Oct-3/4, Klf4, Sox2, c-Myc; OKSM) in selected organs. Here, we report OKSM delivery vectors based on pseudotyped Adeno-associated virus (AAV). Using the AAV-DJ capsid, we could robustly reprogram mouse embryonic fibroblasts with low vector doses. Swapping to AAV8 permitted to efficiently reprogram somatic cells in adult mice by intravenous vector delivery, evidenced by hepatic or extra-hepatic teratomas and iPSC in the blood. Notably, we accomplished full in vivo reprogramming without c-Myc. Most iPSC generated in vitro or in vivo showed transcriptionally silent, intronic or intergenic vector integration, likely reflecting the increased host genome accessibility during reprogramming. Our approach crucially advances in vivo reprogramming technology, and concurrently facilitates investigations into the mechanisms and consequences of AAV persistence.
The effectiveness of virtual reality based interventions for symptoms of anxiety and depression: A meta-analysis
Authors: Fodor Liviu A. , Coteț Carmen D. , Cuijpers Pim , Szamoskozi Ștefan , David Daniel , Cristea Ioana A.
Published: July 2018

We report a meta-analysis of virtual reality (VR) interventions for anxiety and depression outcomes, as well as treatment attrition. We included randomized controlled trials comparing VR interventions, alone or in combination, to control conditions or other active psychological interventions. Effects sizes (Hedges’ g) for anxiety and depression outcomes, as post-test and follow-up, were pooled with a random-effects model. Drop-outs were compared using odds ratio (OR) with a Mantel-Haenszel model. We included 39 trials (52 comparisons). Trial risk of bias was unclear for most domains, and high for incomplete outcome data. VR-based therapies were more effective than control at post-test for anxiety, g = 0.79, 95% CI 0.57 to 1.02, and depression, g = 0.73, 95% CI 0.25 to 1.21, but not for treatment attrition, OR = 1.34, 95% CI 0.95 to 1.89. Heterogeneity was high and there was consistent evidence of small study effects. There were no significant differences between VR-based and other active interventions. VR interventions outperformed control conditions for anxiety and depression but did not improve treatment drop-out. High heterogeneity, potential publication bias, predominant use of waitlist controls, and high or uncertain risk of bias of most trials question the reliability of these effects.
Mass Cytometry Reveals Distinct Platelet Subtypes in Healthy Subjects and Novel Alterations in Surface Glycoproteins in Glanzmann Thrombasthenia
Authors: Blair Thomas A. , Michelson Alan D. , Frelinger Andrew L.
Published: July 2018

Mass cytometry (MC) uses mass spectrometry to simultaneously detect multiple metal-conjugated antibodies on single cells, thereby enabling the detailed study of cellular function. Here, for the first time, we applied MC to the analysis of platelets. We developed a panel of 14 platelet-specific metal-tagged antibodies (targeting cluster of differentiation [CD] 9, CD29, CD31, CD36, CD41, CD42a, CD42b, CD61, CD62P, CD63, CD107a, CD154, glycoprotein [GP] VI and activated integrin αIIbβ3) and compared this panel with two fluorescence flow cytometry (FFC) panels (CD41, CD42b, and CD61; or CD42b, CD62P, and activated integrin αIIbβ3) in the evaluation of activation-dependent changes in glycoprotein expression on healthy subject and Glanzmann thrombasthenia (GT) platelets. High-dimensional analysis of surface markers detected by MC identified previously unappreciated subpopulations of platelets in healthy donors. As expected, MC and FFC revealed that GT platelets had significantly reduced CD41, CD61, and activated integrin αIIbβ3 surface expression. MC also revealed that surface expression of CD9, CD42a and CD63 were elevated, CD31, CD154 and GPVI were reduced and CD29, CD36, CD42b, CD62P and CD107a were similar on GT platelets compared to healthy donor platelets. In summary, MC revealed distinct platelet subtypes in healthy subjects and novel alterations in surface glycoproteins on GT platelets.
Lateral optical confinement of GaN-based VCSEL using an atomically smooth monolithic curved mirror
Authors: Hamaguchi Tatsushi , Tanaka Masayuki , Mitomo Jugo , Nakajima Hiroshi , Ito Masamichi , Ohara Maho , Kobayashi Noriko , Fujii Kentaro , Watanabe Hideki , Satou Susumu , Koda Rintaro , Narui Hironobu
Published: July 2018

We demonstrate the lateral optical confinement of GaN-based vertical-cavity surface-emitting lasers (GaN-VCSELs) with a cavity containing a curved mirror that is formed monolithically on a GaN wafer. The output wavelength of the devices is 441–455 nm. The threshold current is 40 mA (Jth = 141 kA/cm2) under pulsed current injection (Wp = 100 ns; duty = 0.2%) at room temperature. We confirm the lateral optical confinement by recording near-field images and investigating the dependence of threshold current on aperture size. The beam profile can be fitted with a Gaussian having a theoretical standard deviation of σ = 0.723 µm, which is significantly smaller than previously reported values for GaN-VCSELs with plane mirrors. Lateral optical confinement with this structure theoretically allows aperture miniaturization to the diffraction limit, resulting in threshold currents far lower than sub-milliamperes. The proposed structure enabled GaN-based VCSELs to be constructed with cavities as long as 28.3 µm, which greatly simplifies the fabrication process owing to longitudinal mode spacings of less than a few nanometers and should help the implementation of these devices in practice.
N-mixture models reliably estimate the abundance of small vertebrates
Authors: Ficetola Gentile Francesco , Barzaghi Benedetta , Melotto Andrea , Muraro Martina , Lunghi Enrico , Canedoli Claudia , Lo Parrino Elia , Nanni Veronica , Silva-Rocha Iolanda , Urso Arianna , Carretero Miguel Angel , Salvi Daniele , Scali Stefano , Scarì Giorgio , Pennati Roberta , Andreone Franco , Manenti Raoul
Published: July 2018

Accurate measures of species abundance are essential to identify conservation strategies. N-mixture models are increasingly used to estimate abundance on the basis of species counts. In this study we tested whether abundance estimates obtained using N-mixture models provide consistent results with more traditional approaches requiring capture (capture-mark recapture and removal sampling). We focused on endemic, threatened species of amphibians and reptiles in Italy, for which accurate abundance data are needed for conservation assessments: the Lanza’s Alpine salamander Salamandra lanzai, the Ambrosi’s cave salamander Hydromantes ambrosii and the Aeolian wall lizard Podarcis raffonei. In visual counts, detection probability was variable among species, ranging between 0.14 (Alpine salamanders) and 0.60 (cave salamanders). For all the species, abundance estimates obtained using N-mixture models showed limited differences with the ones obtained through capture-mark-recapture or removal sampling. The match was particularly accurate for cave salamanders in sites with limited abundance and for lizards, nevertheless non-incorporating heterogeneity of detection probability increased bias. N-mixture models provide reliable abundance estimates that are comparable with the ones of more traditional approaches, and offer additional advantages such as a smaller sampling effort and no need of manipulating individuals, which in turn reduces the risk of harming animals and spreading diseases.
Annexins induce curvature on free-edge membranes displaying distinct morphologies
Authors: Boye Theresa Louise , Jeppesen Jonas Camillus , Maeda Kenji , Pezeshkian Weria , Solovyeva Vita , Nylandsted Jesper , Simonsen Adam Cohen
Published: July 2018

Annexins are a family of proteins characterized by their ability to bind anionic membranes in response to Ca2+-activation. They are involved in a multitude of cellular functions including vesiculation and membrane repair. Here, we investigate the effect of nine annexins (ANXA1-ANXA7, ANXA11, ANXA13) on negatively charged double supported membrane patches with free edges. We find that annexin members can be classified according to the membrane morphology they induce and matching a dendrogam of the annexin family based on full amino acid sequences. ANXA1 and ANXA2 induce membrane folding and blebbing initiated from membrane structural defects inside patches while ANXA6 induces membrane folding originating both from defects and from the membrane edges. ANXA4 and ANXA5 induce cooperative roll-up of the membrane starting from free edges, producing large rolls. In contrast, ANXA3 and ANXA13 roll the membrane in a fragmented manner producing multiple thin rolls. In addition to rolling, ANXA7 and ANXA11 are characterized by their ability to form fluid lenses localized between the membrane leaflets. A shared feature necessary for generating these morphologies is the ability to induce membrane curvature on free edged anionic membranes. Consequently, induction of membrane curvature may be a significant property of the annexin protein family that is important for their function.
Integrated Brain Atlas for Unbiased Mapping of Nervous System Effects Following Liraglutide Treatment
Authors: Salinas Casper Bo Gravesen , Lu Tess Tsai-Hsiu , Gabery Sanaz , Marstal Kasper , Alanentalo Tomas , Mercer Aaron Jeffrey , Cornea Anda , Conradsen Knut , Hecksher-Sørensen Jacob , Dahl Anders Bjorholm , Knudsen Lotte Bjerre , Secher Anna
Published: July 2018

Light Sheet Fluorescence Microscopy (LSFM) of whole organs, in particular the brain, offers a plethora of biological data imaged in 3D. This technique is however often hindered by cumbersome non-automated analysis methods. Here we describe an approach to fully automate the analysis by integrating with data from the Allen Institute of Brain Science (AIBS), to provide precise assessment of the distribution and action of peptide-based pharmaceuticals in the brain. To illustrate this approach, we examined the acute central nervous system effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Peripherally administered liraglutide accessed the hypothalamus and brainstem, and led to activation in several brain regions of which most were intersected by projections from neurons in the lateral parabrachial nucleus. Collectively, we provide a rapid and unbiased analytical framework for LSFM data which enables quantification and exploration based on data from AIBS to support basic and translational discovery.
Repurposing drugs to target the malaria parasite unfolding protein response
Authors: Chen Yun , Murillo-Solano Claribel , Kirkpatrick Melanie G. , Antoshchenko Tetyana , Park Hee-Won , Pizarro Juan C.
Published: July 2018

Drug resistant Plasmodium falciparum parasites represent a major obstacle in our efforts to control malaria, a deadly vector borne infectious disease. This situation creates an urgent need to find and validate new drug targets to contain the spread of the disease. Several genes associated with the unfolded protein response (UPR) including Glucose-regulated Protein 78 kDa (GRP78, also known as BiP) have been deemed potential drug targets. We explored the drug target potential of GRP78, a molecular chaperone that is a regulator of the UPR, for the treatment of P. falciparum parasite infection. By screening repurposed chaperone inhibitors that are anticancer agents, we showed that GRP78 inhibition is lethal to drug-sensitive and -resistant P. falciparum parasite strains in vitro. We correlated the antiplasmodial activity of the inhibitors with their ability to bind the malaria chaperone, by characterizing their binding to recombinant parasite GRP78. Furthermore, we determined the crystal structure of the ATP binding domain of P. falciparum GRP78 with ADP and identified structural features unique to the parasite. These data suggest that P. falciparum GRP78 can be a valid drug target and that its structural differences to human GRP78 emphasize potential to generate parasite specific compounds.
Glucose and glutamine handling in the Sertoli cells of transgenic rats overexpressing regucalcin: plasticity towards lactate production
Authors: Mateus Inês , Feijó Mariana , Espínola Luís M. , Vaz Cátia V. , Correia Sara , Socorro Sílvia
Published: July 2018

Sertoli cells (SCs) possess the unparalleled ability to provide the germ line with growth factors and nutrients. Although SCs can oxidize amino acids, e.g., glutamine, they mostly metabolize glucose, producing high amounts of lactate, the germ cells preferential substrate. Regucalcin (RGN) is a calcium-binding protein that has been indicated as a regulator of cell metabolism. In this study, we investigated glucose and glutamine handling in the SCs of transgenic rats overexpressing RGN (Tg-RGN) comparatively with wild-type (Wt) littermates. Primary SCs isolated from adult Tg-RGN animals and maintained in culture for 24 hours, produced and exported more lactate, despite consuming less glucose. These observations were underpinned by increased expression of alanine transaminase, and augmented glutamine consumption, suggesting that alternative routes are contributing to the enhanced lactate production in the SCs of Tg-RGN rats. Moreover, lactate seems to be used by germ cells, with diminished apoptosis being detected in the seminiferous tubules of Tg-RGN animals cultured ex vivo. The obtained results showed a distinct metabolism in the SCs of Wt and Tg-RGN rats widening the roles assigned to RGN in spermatogenesis. These findings also highlighted the plasticity of SCs metabolism, a feature that would be exploited in the context of male infertility.
Comparison of Systematic Ticagrelor-Based Dual Antiplatelet Therapy to Selective Triple Antithrombotic Therapy for Left Ventricle Dysfunction Following Anterior STEMI
Authors: Bastiany Alexandra , Matteau Alexis , El-Turaby Fady , Angers-Goulet Alexandre , Mansour Samer , Daneault Benoit , Potter Brian J.
Published: July 2018

Antithrombotic management of STEMI patients with apical dysfunction, but without demonstrable thrombus, is controversial. Triple antithrombotic therapy (TATT, defined as the addition of oral anticoagulation to dual antiplatelet therapy, or DAPT) may be associated with increased bleeding, while DAPT alone may not adequately protect against cardio-embolic events. We undertook a dual-center study of anterior STEMI patients treated with primary PCI (pPCI) from 2013 to 2015 and presenting presumed new apical dysfunction. The Centre hospitalier de l’Université de Montréal (CHUM) uses a strategy of selective TATT, whereas the Centre hospitalier universitaire de Sherbrooke (CHUS) has favored ticagrelor-based DAPT for all patients since 2013. The primary composite outcome consisted of death, MI, stroke, revascularization, and BARC 3 to 5 bleeding up to 4-months follow-up. We identified 177 cases (69 CHUM; 108 CHUS). Baseline characteristics were similar and procedural success was high (97%). There was no difference in post-procedure LVEF (39 ± 9% vs 37 ± 9%) or the extent of apical dysfunction. The primary composite outcome occurred in 27% with the selective TATT strategy compared to 19% with ticagrelor-DAPT (p = 0.342). Thus, this retrospective dual-center analysis does not support a strategy of conventional TATT over ticagrelor-based DAPT for patients with apical dysfunction following anterior STEMI treated with pPCI. A pragmatic randomized trial is needed to provide a definitive answer to this clinical conundrum.
Bacillus amyloliquefaciens strain MBI600 induces salicylic acid dependent resistance in tomato plants against Tomato spotted wilt virus and Potato virus Y
Authors: Beris Despoina , Theologidis Ioannis , Skandalis Nicholas , Vassilakos Nikon
Published: July 2018

Plant growth promoting rhizobacteria have been proposed as effective biocontrol agents against several fungal and bacterial plant pathogens. However, there is limited knowledge regarding their effect against viruses. In this study, Bacillus amyloliquefaciens strain MBI600 (MBI600), active ingredient of the biological fungicide Serifel® (BASF SE), was tested for its antiviral action in tomato plants. Drench, foliar or soil amendment applications of MBI600 reduced up to 80% the incidence of Tomato spotted wilt virus under two different sets of environmental conditions. In addition, drench application of MBI600 delayed Potato virus Y systemic accumulation. Transcriptional analysis of a range of genes associated with salicylic acid (SA)- or jasmonic acid - related defense, priming or basal defense against viruses, revealed the induction of the SA signaling pathway in tomato after MBI600 treatment, and discrete gene expression patterns in plant response to TSWV and PVY infection.
Data analysis and uncertainty estimation in supercontinuum laser absorption spectroscopy
Authors: Emmert Johannes , Blume Niels Göran , Dreizler Andreas , Wagner Steven
Published: July 2018

A set of algorithms is presented that facilitates the evaluation of super continuum laser absorption spectroscopy (SCLAS) measurements with respect to temperature, pressure and species concentration without the need for simultaneous background intensity measurements. For this purpose a non-linear model fitting approach is employed. A detailed discussion of the influences on the instrument function of the spectrometer and a method for the in-situ determination of the instrument function without additional hardware are given. The evaluation procedure is supplemented by a detailed measurement precision assessment by applying an error propagation through the non-linear model fitting approach. While the algorithms are tailored to SCLAS, they can be transferred to other spectroscopic methods, that similarly require an instrument function. The presented methods are validated using gas cell measurements of methane in the near infrared region at pressures up to 8.7 bar.
Nurse-led hypertension management was well accepted and non-inferior to physician consultation in a Chinese population: a randomized controlled trial
Authors: Yip Benjamin Hon Kei , Lee Eric Kam Pui , Sit Regina Wing Shan , Wong Carmen , Li Xue , Wong Eliza Lai Yi , Wong Martin Chi sang , Chung Roger Yat Nork , Chung Vincent Chi ho , Kung Kenny , Wong Samuel Yeung shan
Published: July 2018

The objective of this study is to evaluate if nurse-led repeated prescription (NRP) could ensure non-inferior disease control and would be accepted in Chinese patients with controlled hypertension (HT) in primary care clinics. A 12-month follow-up non-inferiority randomized trial was conducted. The non-inferior margins for systolic and diastolic blood pressure were 6.6 mmHg and 3.7 mmHg, respectively. Eligible patients (>18 years of age) with HT were randomized to the NRP and usual care (UC) groups for their regular clinical follow-up. We used ANCOVA to study the difference-of-difference of the blood pressures between the two groups. The levels of patient acceptance and experience of NRP were assessed by the observed opt-out rate and a qualitative analysis. We found no statistically significant differences in BP blood pressure between the NRP (N = 194) and UC (N = 199) groups. Only 4 of the participants in the NRP group opted out due to a preference for assessment by a physician. The interviewed participants (N = 12) felt positive about NRP, because they experienced more relaxed communication with the nurse and believed that the eligibility to join the NRP program was an indication of optimal BP control. We observed no adverse events. The findings show that NRP was well accepted and found to be non-inferior to physician consultation for HT management.
Cobra Venom Factor-induced complement depletion protects against lung ischemia reperfusion injury through alleviating blood-air barrier damage
Authors: Haihua Chang , Wei Wang , Kun Huang , Yuanli Liao , Fei Lin
Published: July 2018

The purpose of this study was to study whether complement depletion induced by pretreatment with Cobra Venom Factor (CVF) could protect against lung ischemia reperfusion injury (LIRI) in a rat model and explore its molecular mechanisms. Adult Sprague-Dawley rats were randomly assigned to five groups (n = 6): Control group, Sham-operated group, I/R group, CVF group, I/R + CVF group. CVF (50 μg/kg) was injected through the tail vein 24 h before anesthesia. Lung ischemia reperfusion (I/R) was induced by clamping the left hilus pulmonis for 60 minutes followed by 4 hours of reperfusion. Measurement of complement activity, pathohistological lung injury score, inflammatory mediators, pulmonary permeability, pulmonary edema, integrity of tight junction and blood-air barrier were performed. The results showed that pretreatment with CVF significantly reduced complement activity in plasma and BALF. Evaluation in histomorphology showed that complement depletion induced by CVF significantly alleviated the damage of lung tissues and inhibited inflammatory response in lung tissues and BALF. Furthermore, CVF pretreatment had the function of ameliorating pulmonary permeability and preserving integrity of tight junctions in IR condition. In conclusion, our results indicated that complement depletion induced by CVF could inhibit I/R-induced inflammatory response and alleviate lung I/R injury. The mechanisms of its protective effects might be ameliorated blood-air barrier damage.
A Novel Forming Method of Traditional Chinese Medicine Dispersible Tablets to Achieve Rapid Disintegration Based on the Powder Modification Principle
Authors: Li Pan , Feng Bi , Jiang Hong , Han Xue , Wu Zhenfeng , Wang Yaqi , Lin Junzhi , Zhang Yi , Yang Ming , Han Li , Zhang Dingkun
Published: July 2018

Slow disintegration and poor solubility are common problems facing the dispersible tablets of Traditional Chinese Medicine (TCM). In an early study, the research group found that co-grinding of extracts and silica could achieve a rapid disintegration effect, though the mechanism of this effect was not thoroughly elucidated. In this study, Yuanhu Zhitong dispersible tablets (YZDT) were selected as a model drug to explore the mechanism of rapid disintegration and dissolution. First, eight types of silica were used to prepare modified YZDT, and their disintegration time and amount of dissolution within 5 min were measured. Next, the powder properties of eight types of silica were investigated. By correlation analysis, it was found that the average pore size and density of silica were closely related to the effect of promoting disintegration. It was determined that the co-grinding of silica and extracts provided high porosity for the raw material drug, and its abundant narrow channels provided a strong static pressure for water penetration to achieve a rapid disintegration effect. Meanwhile, it was found that the addition of silica had a certain effect on promoting dissolution. Our results provide a highly operational approach for improving the disintegration and dissolution of TCM dispersible tablets. Meanwhile, this approach is also beneficial for establishing a high-quality evaluation index for silica.
Inactivation of group 2 σ factors upregulates production of transcription and translation machineries in the cyanobacterium Synechocystis sp. PCC 6803
Authors: Koskinen Satu , Hakkila Kaisa , Kurkela Juha , Tyystjärvi Esa , Tyystjärvi Taina
Published: July 2018

We show that the formation of the RNAP holoenzyme with the primary σ factor SigA increases in the ΔsigBCDE strain of the cyanobacterium Synechocystis sp. PCC 6803 lacking all group 2 σ factors. The high RNAP-SigA holoenzyme content directly induces transcription of a particular set of housekeeping genes, including ones encoding transcription and translation machineries. In accordance with upregulated transcripts, ΔsigBCDE contain more RNAPs and ribosomal subunits than the control strain. Extra RNAPs are fully active, and the RNA content of ΔsigBCDE cells is almost tripled compared to that in the control strain. Although ΔsigBCDE cells produce extra rRNAs and ribosomal proteins, functional extra ribosomes are not formed, and translation activity and protein content remained similar in ΔsigBCDE as in the control strain. The arrangement of the RNA polymerase core genes together with the ribosomal protein genes might play a role in the co-regulation of transcription and translation machineries. Sequence logos were constructed to compare promoters of those housekeeping genes that directly react to the RNAP-SigA holoenzyme content and those ones that do not. Cyanobacterial strains with engineered transcription and translation machineries might provide solutions for construction of highly efficient production platforms for biotechnical applications in the future.