bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liver X receptor activation inhibits SGLT2‐mediated glucose transport in human renal proximal tubular cells
Authors: Chonlaket Pattira , Wongwan Teerasak , Soodvilai Sunhapas 
Published: November 2017

New Findings
What is the central question of this study?
The liver X receptor (LXR) has been reported to regulate several membrane transporters. It is imperative to investigate whether LXR activation regulates SGLT2‐mediated glucose transport in human renal proximal tubular cells.

What is the main finding and its importance?
Liver X receptor activation inhibits SGLT2 transport function in normal and high‐glucose conditions via reduction of SGLT2 protein expression.

Liver X receptors (LXRs) are members of a nuclear receptor family consisting of two isoforms, LXRα and LXRβ. They play a major role in energy metabolism, including lipid and glucose metabolism. Recent studies reported that LXRs regulate plasma glucose, although the mechanism is still uncertain. The present study investigated whether LXR activation regulates sodium glucose cotransporter2 (SGLT2) in human renal proximal tubular cells. LXR agonists, T0901317 and GW3965, inhibited SGLT2‐mediated glucose uptake in a concentration‐dependent manner. The effect of T0901317 and GW3965 was attenuated by a LXR antagonist, fenofibrate. Activation of the retinoid X receptor (RXR) agonist, bexarotene, potentiates the inhibitory effect of these ligands. Thus, the inhibitory effect of LXR agonists on SGLT2 was mediated and facilitated by LXR and RXR activation, respectively. In addition, the inhibitory effect of LXR agonists was not mediated by cytotoxicity. Exposing HK‐2 cells, a renal proximal tubular cell line, to LXR agonists significantly reduced the maximal transport rate of SGLT2 without any effect on transporter affinity. Western blot analysis revealed that LXR activation significantly decreased protein expression of SGLT2 with no change in mRNA level. In addition, LXR activation inhibited canagliflozin‐sensitive short‐circuit current, which represents SGLT2‐mediated glucose transport in a polarized human renal proximal tubular cell monolayer. Furthermore, LXR activation inhibited the transport function of SGLT2 in hyperglycaemic conditions. As such, this study represents evidence for the inhibitory effect of LXR activation on glucose transport in human renal proximal tubular cells.
UBC‐Nepal expedition: acclimatization to high‐altitude increases spinal motoneurone excitability during fatigue in humans
Authors: Ruggiero Luca , Yacyshyn Alexandra F. , Nettleton Jane , McNeil Chris J. 
Published: November 2017

Key points
Acute exposure and acclimatization to hypoxia are associated with an impairment and partial recovery, respectively, of the capability of the central nervous system to drive muscles during prolonged efforts.
Motoneurones play a vital role in muscle contraction and in fatigue, although the effect of hypoxia on motoneurone excitability during exercise has not been assessed in humans.
We studied the impact of fatigue on motoneurone excitability in normoxia, acute and chronic exposure (5050 m) to hypoxia.
Performance was worse in acute hypoxia but recovered to the normoxic standard in chronic hypoxia, in parallel with an increased excitability of the motoneurones compared to acute exposure to hypoxia.
These findings reveal that prolonged hypoxia causes a heightened motoneurone responsiveness during fatiguing exercise; such an adaptation might favour the restoration of performance where low pressures of oxygen are chronically present.
AbstractThe fatigue‐induced failure of the motor cortex to drive muscles maximally increases in acute hypoxia (AH) compared to normoxia (N) but improves with acclimatization (chronic hypoxia; CH). Despite their importance to muscle output, it is unknown how locomotor motoneurones in humans are affected by hypoxia and acclimatization. Eleven participants performed 16 min of submaximal [25% maximal torque (maximal voluntary contraction, MVC)] intermittent isometric elbow flexions in N, AH (environmental chamber) and CH (7–14 days at 5050 m) (PIO2 = 140, 74 and 76 mmHg, respectively). For each minute of the fatigue protocol, motoneurone responsiveness was measured with cervicomedullary stimulation delivered 100 ms after transcranial magnetic stimulation (TMS) used to transiently silence voluntary drive. Every 2 min, cortical voluntary activation (cVA) was measured with TMS. After the task, MVC torque declined more in AH (∼20%) than N and CH (∼11% and 14%, respectively, P < 0.05), with no differences between N and CH. cVA was lower in AH than N and CH at baseline (∼92%, 95% and 95%, respectively) and at the end of the protocol (∼82%, 90% and 90%, P < 0.05). During the fatiguing task, motoneurone excitability in N and AH declined to ∼65% and 40% of the baseline value (P < 0.05). In CH, motoneurone excitability did not decline and, late in the protocol, was ∼40% higher compared to AH (P < 0.05). These novel data reveal that acclimatization to hypoxia leads to a heightened motoneurone responsiveness during fatiguing exercise. Positive spinal and supraspinal adaptations during extended periods at altitude might therefore play a vital role for the restoration of performance after acclimatization to hypoxia.
Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection
Authors: Ekins Sean , Lingerfelt Mary A. , Comer Jason E. , Freiberg Alexander N. , Mirsalis Jon C. , O'Loughlin Kathleen , Harutyunyan Anush , McFarlane Claire , Green Carol E. , Madrid Peter B. 
Published: November 2017

ABSTRACT

Tilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside the United States. A machine-learning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potent
in vitro
EBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series of
in vitro
ADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate, and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9, and 1A2). Tilorone was shown to have 52% human plasma protein binding with excellent plasma stability and a mouse liver microsome half-life of 48 min. Dose range-finding studies in mice demonstrated a maximum tolerated single dose of 100 mg/kg of body weight. A pharmacokinetics study in mice at 2- and 10-mg/kg dose levels showed that the drug is rapidly absorbed, has dose-dependent increases in maximum concentration of unbound drug in plasma and areas under the concentration-time curve, and has a half-life of approximately 18 h in both males and females, although the exposure was ∼2.5-fold higher in male mice. Tilorone doses of 25 and 50 mg/kg proved efficacious in protecting 90% of mice from a lethal challenge with mouse-adapted with once-daily intraperitoneal (i.p.) dosing for 8 days. A subsequent study showed that 30 mg/kg/day of tilorone given i.p. starting 2 or 24 h postchallenge and continuing through day 7 postinfection was fully protective, indicating promising activity for the treatment of EVD.
Mutations in Gene
fusA1
as a Novel Mechanism of Aminoglycoside Resistance in Clinical Strains of Pseudomonas aeruginosa
Authors: Bolard Arnaud , Plésiat Patrick , Jeannot Katy 
Published: November 2017

ABSTRACT

Resistance of clinical strains of
Pseudomonas aeruginosa
to aminoglycosides can result from production of transferable aminoglycoside-modifying enzymes, of 16S rRNA methylases, and/or mutational derepression of intrinsic multidrug efflux pump MexXY(OprM). We report here the characterization of a new type of mutant that is 4- to 8-fold more resistant to 2-deoxystreptamine derivatives (e.g., gentamicin, amikacin, and tobramycin) than the wild-type strain PAO1. The genetic alterations of three
in vitro
mutants were mapped on
fusA1
and found to result in single amino acid substitutions in domains II, III, and V of elongation factor G (EF-G1A), a key component of translational machinery. Transfer of the mutated
fusA1
alleles into PAO1 reproduced the resistance phenotype. Interestingly,
fusA1
mutants with other amino acid changes in domains G, IV, and V of EF-G1A were identified among clinical strains with decreased susceptibility to aminoglycosides. Allelic-exchange experiments confirmed the relevance of these latter mutations and of three other previously reported alterations located in domains G and IV. Pump MexXY(OprM) partly contributed to the resistance conferred by the mutated EF-G1A variants and had additive effects on aminoglycoside MICs when mutationally upregulated. Altogether, our data demonstrate that cystic fibrosis (CF) and non-CF strains of
P. aeruginosa
can acquire a therapeutically significant resistance to important aminoglycosides via a new mechanism involving mutations in elongation factor EF-G1A.
Differentiation of quantitative CT imaging phenotypes in asthma versus COPD
Authors: Choi Sanghun , Haghighi Babak , Choi Jiwoong , Hoffman Eric A , Comellas Alejandro P , Newell John D , Wenzel Sally E , Castro Mario , Fain Sean B , Jarjour Nizar N , Schiebler Mark L , Barr R Graham , Han MeiLan K , Bleecker Eugene R , Cooper Christopher B , Couper David , Hansel Nadia , Kanner Richard E , Kazerooni Ella A , Kleerup Eric A C , Martinez Fernando J , O’Neal Wanda K , Woodruff Prescott G , Lin Ching-Long 
Published: November 2017

IntroductionQuantitative CT (QCT) imaging-based metrics have quantified disease alterations in asthma and chronic obstructive pulmonary disease (COPD), respectively. We seek to characterise the similarity and disparity between these groups using QCT-derived airway and parenchymal metrics.MethodsAsthma and COPD subjects (former-smoker status) were selected with a criterion of post-bronchodilator FEV1<80%. Healthy non-smokers were included as a control group. Inspiratory and expiratory QCT images of 75 asthmatic, 215 COPD and 94 healthy subjects were evaluated. We compared three segmental variables: airway circularity, normalised wall thickness and normalised hydraulic diameter, indicating heterogeneous airway shape, wall thickening and luminal narrowing, respectively. Using an image registration, we also computed six lobar variables including per cent functional small-airway disease, per cent emphysema, tissue fraction at inspiration, fractional-air-volume change, Jacobian and functional metric characterising anisotropic deformation.ResultsCompared with healthy subjects, both asthma and COPD subjects demonstrated a decreased airway circularity especially in large and upper lobar airways, and a decreased normalised hydraulic diameter in segmental airways. Besides, COPD subjects had more severe emphysema and small-airway disease, as well as smaller regional tissue fraction and lung deformation, compared with asthmatic subjects. The difference of emphysema, small-airway disease and tissue fraction between asthma and COPD was more prominent in upper and middle lobes.ConclusionsPatients with asthma and COPD, with a persistent FEV1<80%, demonstrated similar alterations in airway geometry compared with controls, but different degrees of alterations in parenchymal regions. Density-based metrics measured at upper and middle lobes were found to be discriminant variables between patients with asthma and COPD.
Conference presentation in palliative medicine: predictors of subsequent publication
Authors: Hanchanale Sarika , Kerr Maria , Ashwood Paul , Curran Emily , Ekstrom Magnus , Allen Sharon , Currow David , Johnson Miriam J 
Published: November 2017

ObjectivesConcerns have been raised about poor-quality palliative care research and low publication rate from conference abstracts. The study objectives: to estimate the publication rate for European Association for Palliative Care research conference abstracts (2008) and explore associated characteristics and to understand reasons for non-publication.MethodsFull published papers were searched to March 2015 (Medline; Pubmed; Google Scholar) and data extracted: country of origin, study design/population/topic. Multivariate logistic regression was used to identify predictors of publication.Members of two different palliative care associations were surveyed to understand reasons for non-publication. χ2statistic was used to explore associations with publication.ResultsOverall publication rate of the 445 proffered abstracts was 57%. In the final model, publication was more likely for oral presentations (OR 2.13; 95% CI 1.28 to 3.55; P=0.003), those from Europe (3.24; 1.09 to 9.56; P=0.033) and much less likely for non-cancer topics (0.21; 0.07 to 0.64; P=0.006). Funding status, academic unit or study design were not associated with publication.Survey407/1546 (26.3%) physicians responded of whom 254 (62%) had submitted a conference abstract. Full publication was associated with: oral presentation (P<0.001), international conference abstracts (P=0.01) and academic clinicians versus clinicians (P<0.001). Reasons for non-publication included: low priority for workload (53%) and time constraints (43%).ConclusionsThe publication rate was similar to 2005 clinical conference. Probable quality markers were associated with publication: oral presentations selected by conference committee, international conference abstracts and abstracts from those with an academic appointment. Publication was given a low priority among clinical time pressures.
Microcatheter contrast injection in stent retriever neurothrombectomy is safe and useful: insights from SWIFT PRIME
Authors: Raychev Radoslav , Jahan Reza , Saver Jeffrey L , Nogueira Raul G , Goyal Mayank , Pereira Vitor M , Levy Elad , Yavagal Dileep R , Cognard Christophe , Liebeskind David 
Published: November 2017

Microcatheter contrast injection (MCI) prior to stent retriever deployment for the treatment of acute ischemic stroke may be useful for evaluation of distal anatomy and flow patterns beyond the occlusion. However, prior data from intra-arterialthrombolysis suggested that MCI increases the risk of intracranial hemorrhage (ICH). The safety and utility of MCI has not been investigated in the setting of thrombectomy.MethodsWe analyzed the Solitaire With the Intention For Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) trial to correlate pre-intervention MCI flow with collateral flow, and to investigate its impact on ICH and clinical outcome after thrombectomy with the Solitaire device.ResultsMCI was noted in 52% (n=51) of patients with a prevalence for the M2 location of 71% (n=36). Dichotomized correlation demonstrated a strong inverse relationship for partial collaterals with good MCI flow (p=0.004; OR 8.25). None of the MCI variables (presence, number, or grades) correlated with ICH and clinical outcome. The most significant predictors of non-disabled outcome were higher Alberta Stroke Program early CT Score (ASPECTS) (OR 1.61; p=0.0361) and younger age (OR 0.922; p = 0.0109). Higher ASPECTS was also a strong predictor of lower ICH risk (OR 0.501, p=0.0078).ConclusionsCollateral flow inversely correlated with MCI flow in the endovascular arm of the SWIFT PRIME trial. This finding warrants further validation in larger cohorts as MCI may be influenced by individual operator’s technique and choice of syringe size. Evaluation of flow and distal anatomy with MCI prior to stent retriever deployment is safe with no evidence of an impact on ICH or clinical outcome.Clinical trial registrationNCT01657461: Post- results
Dump the pump: manual aspiration thrombectomy (MAT) with a syringe is technically effective, expeditious, and cost-efficient
Authors: Gross Bradley A , Jadhav Ashutosh P , Jovin Tudor G , Jankowitz Brian Thomas 
Published: November 2017

IntroductionSyringe aspiration for manual aspiration thrombectomy (MAT) is a cost- and time-efficient alternative to an aspiration pump with likely similar efficacy. It is counterintuitive to expect the pump to perform better than direct vacuum with a syringe, as the pump must deliver vacuum additionally through a canister and meters of tubing.ObjectiveTo present in vitro and clinical results of MAT with a syringe.MethodsAn in vitro analysis was performed comparing vacuum pressures generated by syringe aspiration and with pump aspiration. This was then complemented with prospective clinical data providing details of angiographic and clinical outcomes for syringe MAT.ResultsThe in vitro analysis demonstrated that equal to slightly greater vacuum pressures were generated by a 60 cc syringe as compared with the pump in both static and partial flow conditions. In our clinical series, 106/113 acute stroke thrombectomies over a 6-month period were performed with syringe MAT on the first pass. Syringe usage instead of pump tubing and a canister led to a total savings of $58 300. The rate of Thrombolysis in Cerebral Infarction 2b/3 recanalization was 93%. Adjunctive stentriever usage was performed in 23% of cases. Median puncture to reperfusion time was 25 min; mean change in National Institute of Health Stroke Scale score at 24 hours was an improvement of 5.1 (median 6). The in-hospital mortality rate was 10%. Seventy percent of patients were discharged to home (modified Rankin Scale (mRS) score 0–2) or a rehabilitation facility (mRS score 2–4).ConclusionMAT using a syringe is a safe, fast, and more cost-effective approach than using an aspiration pump.
Inversion for Biot-consistent material properties in subresonant oscillation experiments with fluid-saturated porous rock
Authors: Morozov Igor B. , Deng Wubing 
Published: November 2017

To quantitatively interpret the results of a subresonant laboratory or numerical experiment with wet porous rock, it is insufficient to merely state the measured frequency-dependent viscoelastic moduli and [Formula: see text]-factors. The measured properties are apparent, i.e., dependent on the experimental setup such as the length of the sample and boundary conditions for pore flows. To reveal the true properties of the material, all experimental factors need to be accurately modeled and corrected for. Here, such correction is performed by developing an effective Biot’s model for the material and using it to predict driven oscillations of a cylindrical rock specimen. The model explicitly describes elastic and inertial effects, Biot’s flows, and viscous internal friction within the solid frame and pore fluid, and it approximates squirt and other wave-induced flow effects. The model predicts the dynamic permeability of the specimen, fast (traveling) and slow (diffusive) P- and axial-deformation waves, and it allows accurate modeling of any other ultrasonic or seismic-frequency experiments with the same rock. To illustrate the approach, attenuation and dispersion data from two laboratory and numerical experiments with sandstones are inverted for effective, frequency-dependent moduli of drained sandstone. Several observations from this inversion may be useful for interpreting experiments with porous rock. First, Young’s moduli measured in a short rock cylinder differ from those in a traveling wave within an infinite rod. In particular, for the modeled 8 cm long rock specimen, modulus dispersion and attenuation ([Formula: see text]) are approximately 10 times greater than for a traveling wave. Second, P-wave moduli cannot be derived from the measured Young’s and shear moduli by using conventional (visco)elastic relations. Third, because of wavelengths comparable with the size of the specimen, slow waves contribute to its quasistatic and low-frequency behaviors. Similar observations should also apply to seismic waves traveling through approximately 10 cm layering in the field.
AMBIENTE DE INOVAÇÃO: ESTUDO COMPARATIVO ENTRE TRÊS UNIDADES DE UMA ORGANIZAÇÃO DO SETOR METAL-MECÂNICO
Authors: De Carvalho Luciano Castro , Netto Machado Denise Del Pra 
Published: November 2017

Conhecer os fatores motivacionais ao desenvolvimento dos processos de inovação tem despertado interesse na área de estudos organizacionais e tem se apresentado como desafio para o campo da Gestão. Sendo assim, buscou-se neste trabalho identificar as semelhanças/diferenças nas características do ambiente inovador nas três unidades da empresa que ganhou por dois anos consecutivos o prêmio FINEP de inovação e listada pela Revista Época em 2008 como uma das cem melhores empresas para se trabalhar e verificar se as características percebidas por esses ambientes possuem aderência ao modelo proposto pelo Minnesota Innovation Research Program (MIRP) com base na metodologia Minnesota Innovation Survey (MIS). Foram pesquisados 349 funcionários dispersos geograficamente entre as três filiais localizadas nos estados do Rio Grande do Sul, Goiás e São Paulo. Os sujeitos sociais responderam um questionário adaptado do modelo, desenvolvido pelo (MIRP) com base na metodologia MIS, contendo três grupos de dimensões que envolvem características internas, externas e de resultados, totalizando 21 dimensões e englobando 45 questões com opções de resposta em escala Likert de cinco pontos. Foi utilizado o alfa de Cronbach, análise de freqüência e a modelagem de equações estruturais como ferramentas de análise. Como resultados apurou-se que das 21 dimensões estudadas, 10 foram percebidas de forma comum as três unidades como constantes de um ambiente favorável ao desenvolvimento de inovações e 7 não foram percebidas como existentes no ambiente estudado. No total das 21 dimensões, 17 obtiveram percepções comuns, embora em frequência diferentes. Verificou-se nas três unidades que a participação que o fator que caracteriza o ambiente de inovação refere-se a participação dos empregados no processo de tomada de decisão sobre inovações. De uma forma geral pode-se afirmar que as unidades possuem mais semelhanças do que diferenças e que a unidade de Goiás teve melhor adesão ao modelo proposto pelo MIRP devido as correlações existentes entre dimensões internas e externas sobre a percepção de eficiência da inovação. Assim, conforme a metodologia MIS, as unidades de Goiás e Rio Grande do Sul apresentam evidências de ser a mais e menos inovadora, respectivamente.
Editorial
Authors: Editorial REGEPE 
Published: November 2017

Temos muita satisfação de publicar um novo número da REGEPE. Iniciando o segundo volume, trazemos para apreciação da comunidade acadêmica mais seis artigos. O tema predominante dessa edição é a inovação, foco de três artigos. Sustentabilidade, competivididade e perfil empreendedor completam o leque de temas presentes nesse número da REGEPE. Vargas, Bohrer, Ferreira e Moreira demonstram, em seu trabalho, o estado da arte da pesquisa sobre inovação em serviços no Brasil. Além disso, ao comparar os resultados com o estágio atual da pesquisa internacional, revelaram limites da pesquisa brasileira nesse tema. Por fim, os autores apontam desafios que se apresentam para a comunidade acadêmica brasileira dedicada ao tema, sugerindo uma agenda de pesquisa. Mendes, Oliveira e Pinheiro abordam os impactos da Política Nacional de Ciência, Tecnologia e Inovação sobre os indicadores do processo inovativo. A partir do estabelecimento de marco regulatório pelas Lei da Inovação e Lei do Bem, os autores buscaram evidências sobre a evolução e um dos investimentos privados em P&D no Brasil.