bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose prediction for repurposing nitazoxanide in SARS‐CoV‐2 treatment or chemoprophylaxis
Authors: Rajoli Rajith K. R. , Pertinez Henry , Arshad Usman , Box Helen , Tatham Lee , Curley Paul , Neary Megan , Sharp Joanne , Liptrott Neill J. , Valentijn Anthony , David Christopher , Rannard Steven P. , Aljayyoussi Ghaith , Pennington Shaun H. , Hill Andrew , Boffito Marta , Ward Steve A. , Khoo Saye H. , Bray Patrick G. , O'Neill Paul M. , Hong W. David , Biagini Giancarlo A. , Owen Andrew 
Published: October 2020

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS‐CoV‐2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS‐CoV‐2 EC90.MethodsA whole‐body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials.ResultsThe PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated.ConclusionThe PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS‐CoV‐2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.
Population pharmacokinetics of propofol in neonates and infants: Gestational and postnatal age to determine clearance maturation
Authors: Sandra Louis , Smits Anne , Allegaert Karel , Nicolaï Johan , Annaert Pieter , Bouillon Thomas 
Published: October 2020

AimsDevelop a population pharmacokinetic model describing propofol pharmacokinetics in (pre)term neonates and infants, that can be used for precision dosing (e.g. during target‐controlled infusion) of propofol in this population.MethodsA nonlinear mixed effects pharmacokinetic analysis (Monolix 2018R2) was performed, based on a pooled study population in 107 (pre)term neonates and infants.ResultsIn total, 836 blood samples were collected from 66 (pre)term neonates and 41 infants originating from 3 studies. Body weight (BW) of the pooled study population was 3.050 (0.580–11.440) kg, postmenstrual age (PMA) was 36.56 (27.00–43.00) weeks and postnatal age (PNA) was 1.14 (0–104.00) weeks (median and min‐max range). A 3‐compartment structural model was identified and the effect of BW was modelled using fixed allometric exponents. Elimination clearance maturation was modelled accounting for the maturational effect on elimination clearance until birth (by gestational age [GA]) and postpartum (by PNA and GA). The extrapolated adult (70 kg) population propofol elimination clearance (1.64 L min−1, estimated relative standard error = 6.02%) is in line with estimates from previous population pharmacokinetic studies. Empirical scaling of BW on the central distribution volume in function of PNA improved the model fit.ConclusionsIt is recommended to describe elimination clearance maturation by GA and PNA instead of PMA on top of size effects when analyzing propofol pharmacokinetics in populations including preterm neonates. Changes in body composition in addition to weight changes or other physio‐anatomical changes may explain the changes in central distribution volume. The developed model may serve as a prior for propofol dose finding and target‐controlled infusion in (preterm) neonates.
Regulation of hepatic stellate cell contraction and cirrhotic portal hypertension by Wnt/β‐catenin signalling via interaction with Gli1
Authors: Zhang Feng , Wang Feixia , He Jianlin , Lian Naqi , Wang Zhenyi , Shao Jiangjuan , Ding Hai , Tan Shanzhong , Chen Anping , Zhang Zili , Wang Shijun , Zheng Shizhong 
Published: October 2020

Background and PurposePortal hypertension is a lethal complication of cirrhosis. Its mechanism and therapeutic targets remain largely unknown. Hepatic stellate cell (HSC) contraction increases intrahepatic vascular resistance contributing to portal hypertension. We investigated how HSC contraction was regulated by Wnt signalling and the therapeutic implications.Experimental ApproachLiver tissues from cirrhotic patients were examined. Cirrhotic mice with genetic or pharmacological treatments were used for in vivo assessments, and their primary cells were isolated. Cellular functions and signalling pathways were analysed in human HSC‐LX2 cells using real‐time PCR, Western blotting, siRNA, luciferase reporter assay, chromatin immunoprecipitation, co‐immunoprecipitation and site‐directed mutagenesis.Key ResultsWnt/β‐catenin correlated with HSC contraction in human cirrhotic liver. Wnt3a stimulated Smo‐independent Gli1 nuclear translocation followed by LARG‐mediated RhoA activation leading to HSC contraction. Suppressor of fused (Sufu) negatively mediated Wnt3a‐induced Gli1 nuclear translocation. Wnt/β‐catenin repressed transcription of Sufu dependent on β‐catenin/TCF4 interaction and TCF4 binding to Sufu promoter. Molecular simulation and site‐directed mutagenesis identified the β‐catenin residues Lys312 and Lys435 critically involved in this interaction. TCF4 binding to the sequence CACACCTTCC at Sufu promoter was required for transrepression of Sufu. In cirrhotic mice, short‐term liver‐targeting β‐catenin deficiency or acute treatment with β‐catenin inhibitors reduced portal pressure via restriction of HSC contraction rather than inhibiting HSC activation. Long‐term deficiency or treatments also ameliorated liver injury, fibrosis and inflammation.Conclusion and ImplicationsInteraction between Wnt/β‐catenin and Smo‐independent Gli1 pathways promoted HSC contraction via TCF4‐dependent transrepression of Sufu. HSC‐specific inhibition of β‐catenin may have therapeutic benefits for cirrhotic portal hypertension.
A novel class of fast‐acting antimalarial agents: Substituted 15‐membered azalides
Authors: Peric Mihaela , Pešić Dijana , Alihodžić Sulejman , Fajdetić Andrea , Herreros Esperanza , Gamo Francisco Javier , Angulo‐Barturen Iñigo , Jiménez‐Díaz María Belén , Ferrer‐Bazaga Santiago , Martínez María S. , Gargallo‐Viola Domingo , Mathis Amanda , Kessler Albane , Banjanac Mihailo , Padovan Jasna , Bencetić Mihaljević Vlatka , Munic Kos Vesna , Bukvić Mirjana , Eraković Haber Vesna , Spaventi Radan 
Published: October 2020

Background and PurposeEfficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low.Experimental ApproachFour compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model.Key ResultsNovel fast‐acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine‐resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin‐containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half‐lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti‐plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow‐acting azithromycin.Conclusion and ImplicationsThe hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy.
AMP‐activated protein kinase activation primes cytoplasmic translocation and autophagic degradation of the BCR‐ABL protein in CML cells
Authors: Koyama Daisuke , Kikuchi Jiro , Kuroda Yoshiaki , Ohta Masatsugu , Furukawa Yusuke 
Published: October 2020

AbstractChronic myeloid leukemia is driven by the BCR‐ABL oncoprotein, a constitutively active protein tyrosine kinase. Although tyrosine kinase inhibitors (TKIs) have greatly improved the prognosis of CML patients, the emergence of TKI resistance is an important clinical problem, which deserves additional treatment options based on unique biological properties to CML cells. In this study, we show that metabolic homeostasis is critical for survival of CML cells, especially when the disease is in advanced stages. The BCR‐ABL protein activates AMP‐activated protein kinase (AMPK) for ATP production and the mTOR pathway to suppress autophagy. BCR‐ABL is detected in the nuclei of advanced‐stage CML cells, in which ATP is sufficiently supplied by enhanced glucose metabolism. AMP‐activated protein kinase is further activated under energy‐deprived conditions and triggers autophagy through ULK1 phosphorylation and mTOR inhibition. In addition, AMPK phosphorylates 14‐3‐3 and Beclin 1 to facilitate cytoplasmic translocation of nuclear BCR‐ABL in a BCR‐ABL/14‐3‐3τ/Beclin1/XPO1 complex. Cytoplasmic BCR‐ABL protein undergoes autophagic degradation when intracellular ATP is exhausted by disruption of the energy balance or forced autophagy flux with AMP mimetics, mTOR inhibitors, or arsenic trioxide, leading to apoptotic cell death. This pathway represents a novel therapeutic vulnerability that could be useful for treating TKI‐resistant CML.
Age, period and cohort trends in oral health status in South Korean adults
Authors: Kim Eun‐Soo , Kim Baek‐Il , Jung Hoi In 
Published: October 2020

AbstractObjectivesThe purpose of this study was to identify the age, period and cohort effects on the changes in oral health status in South Koreans.MethodsThe age, period and cohort analysis (APC analysis) of the oral health status was conducted using an aggregated age‐by‐time period table. The age‐by‐time period table was formulated using data from the Korea National Oral Health Survey (KNOHS) 2000 and 2006, and the Korea National Health and Nutrition Examination Survey (KNHANES) 2010 and 2015. Two oral health outcomes were measured: the number of teeth and Decayed‐Missing‐Filled Teeth (DMFT) index. Descriptive analysis by graphical representation and partial least square (PLS) regression was used for APC analysis.ResultsBoth graphical description and PLS regression showed age and cohort effects in oral health status with the number of teeth decreasing and the DMFT index increasing with age. No period effects were found in either index. The number of teeth increased in the recent birth cohorts. However, the DMFT index showed a reverse J‐shaped trend, which worsened in recent birth cohorts. The DMFT index increase in the recent cohort was mainly attributed by an increase in the FT index.ConclusionsThe effects of age on the number of teeth and caries highlight the importance of oral health in adulthood. The increased caries experience in recent cohorts may indicate the limitations of the current oral health policy. It would be relevant to explore what determinants cause the changes in oral health status. Future oral health policies should address the new directions to reduce the burden of oral diseases.
Deep brain stimulation of the anterior nuclei of the thalamus relieves basal ganglia dysfunction in monkeys with temporal lobe epilepsy
Authors: Du Tingting , Chen Yingchuan , Shi Lin , Liu Defeng , Liu Yuye , Yuan Tianshuo , Zhang Xin , Zhu Guanyu , Zhang Jianguo 
Published: October 2020

AbstractAimsDeep brain stimulation of the anterior nuclei of the thalamus (ANT‐DBS) is effective in temporal lobe epilepsy (TLE). Previous studies have shown that the basal ganglia are involved in seizure propagation in TLE, but the effects of ANT‐DBS on the basal ganglia have not been clarified.MethodsANT‐DBS was applied to monkeys with kainic acid–induced TLE using a robot‐assisted system. Behavior was monitored continuously. Immunofluorescence analysis and Western blotting were used to estimate protein expression levels in the basal ganglia and the effects of ANT stimulation.ResultsThe seizure frequency decreased after ANT‐DBS. D1 and D2 receptor levels in the putamen and caudate were significantly higher in the ANT‐DBS group than in the epilepsy (EP) model. Neuronal loss and apoptosis were less severe in the ANT‐DBS group. Glutamate receptor 1 (GluR1) in the nucleus accumbens (NAc) shell and globus pallidus internus (GPi) increased in the EP group but decreased after ANT‐DBS. γ‐Aminobutyric acid receptor A (GABAA‐R) decreased and glutamate decarboxylase 67 (GAD67) increased in the GPi of the EP group, whereas the reverse tendencies were observed after ANT‐DBS.ConclusionANT‐DBS exerts neuroprotective effects on the caudate and putamen, enhances D1 and D2 receptor expression, and downregulates GPi overactivation, which enhanced the antiepileptic function of the basal ganglia.
Speaking across boundaries to explore the potential for interdisciplinarity in ecosystem services knowledge production
Authors: Schutter Marleen S. , Hicks Christina C. 
Published: October 2020

AbstractConservation is likely to be most successful if it draws on knowledge from across the natural and social sciences. The ecosystem services concept has been called a boundary object in that it facilitates development of such interdisciplinary knowledge because it offers a common platform for researchers, policy makers, and practitioners. However, a question that remains is to what extent the interdisciplinary knowledge needed is provided by disciplinary diversity within the field. We asked where is knowledge on ecosystem services produced, how interdisciplinary is this knowledge, and which disciplines facilitate the greatest disciplinary integration? We definedinterdisciplinarityas the extent to which published research draws on knowledge that crosses disciplinary borders and used citations as a quantitative indicator of communication among disciplines, based on journal classification. We used disciplinary diversity, richness, and heterocitation as measures of interdisciplinarity and betweenness centrality as a measure of disciplinary integration. Our data set contained 22,153 publications on ecosystem services, published from 1983 to 2018. We found that ecosystem services research matured; average yearly output growth was 33.8%, more than the 8–9% growth in scientific output across all fields. Over time, the network clustering coefficient, measuring connectedness of individual disciplines, rose from 0.388 to 0.727, suggesting increased density in the network of citations. Researchers in the field published more articles (3566 in 2018 alone) across more disciplines (77 unique disciplines in 2018). However, this growth was not mirrored by an increase in the diversity (stable at 0.7–0.9) or richness (averaging 0.35 unique disciplines per citation) of citation patterns. Heterocitation scores, or out‐of‐group citations, for arts, humanities, social sciences, and law ranged from 56% to 64%, which was lower than we expected, although this may serve to protect the integrity of social science disciplines and attract broader engagement from within. Ultimately, a small number of productive disciplines are central to supporting disciplinary integration. However, opportunities exist for conservation practice to draw on a broader field of research, to realize the potential that the diverse body of knowledge of interdisciplinary work offers.
Colour design and non‐image‐forming effects in humans: An open issue
Authors: Rossi Maurizio 
Published: October 2020

AbstractNowadays in industrialised countries, human beings spend 80–90% of their time indoors. Under these conditions the light, the colours, ie the perceived image, differs considerably from the outdoors. But this also influences the NIF (non‐image‐forming) effects on our nervous system, such as regulation of the circadian rhythm and other physiological effects. The risks to health arising from NIF effects are highlighted. Even though extensive neurophysiological research has demonstrated the importance of proper NIF management for human health, use of the latter is virtually absent in the design practice. Therefore, we highlight the unresolved research challenges which prevent the development of complete models, particularly useful in defining lighting and, above all, colours in indoor environments, to correctly manage NIF effects.
Severe harm from others' drinking: A population‐based study on sex differences and the role of one's own drinking habits
Authors: Sundin Erica , Galanti Maria Rosaria , Landberg Jonas , Ramstedt Mats 
Published: October 2020

AbstractIntroduction and AimsDespite the fact that many studies have focused on harm from others' drinking, there is a lack of knowledge regarding severe forms of these harms. This study aimed to assess sex differences in the prevalence of severe harm from others' drinking and sex‐specific associations with one's own drinking.Design and MethodsThe data originated from a Swedish cross‐sectional population survey (n = 15 576). Adjusted odds ratios of self‐reported experiences of severe harm (harmed ‘a lot’) from others' drinking were calculated using logistic regression models. Additive interactions were used to determine sex‐specific associations between own drinking and harm.ResultsThe past‐year prevalence of severe harm from known and unknown drinkers was higher among women (4.9% and 1.8%, respectively) than men (1.9% and 1.2%, respectively). Alcohol dependence predicted such harm for both sexes. No association with severe harm from known drinkers was found for male drinkers and binge drinkers, whereas female drinkers and binge drinkers reported more experiences of such harm. These differences indicated a supper‐additive interaction (RERI: 0.92–1.47) and signs of having alcohol dependence among women indicated an even higher interaction (RERI: 5.37).Discussion and ConclusionsWomen suffer more frequently from severe harm from others' drinking. Men and women report different experiences of severe harm from known people's drinking conditioning on their drinking behaviour. Sex‐specific longitudinal studies are warranted to examine the relation between different behaviours and these harms. Whether these findings hold in settings with different drinking cultures and social norms should be explored.
Patterns of invasive plant abundance in disturbed versus undisturbed forests within three land types over 16 years
Authors: Huebner Cynthia D. 
Published: October 2020

AbstractAimLong‐term monitoring of forest understorey species was used to describe changes in native and invasive exotic plant abundances over time within different disturbed or undisturbed forest types. This information was then used to determine the predictive invasion model (passenger/opportunist, driver or back‐seat driver).LocationCheat Ranger District of the Monongahela National Forest, West Virginia, USA.MethodsUnderstorey vegetation of mature and clear‐cut forests was sampled every 5–6 years for 16 years. Stands were stratified across three land types following a moisture gradient. Invasive plant richness, frequency and abundance were evaluated across land type and disturbance type with general linear mixed models. Change in richness, diversity and abundance of both native and invasive non‐native plants was evaluated as a measure of impact.ResultsThe mesic mature stands had the greatest invasive plant richness, frequency and abundance. The moderately mesic clear‐cut stands initially showed the greatest invasive plant richness, frequency and abundance, but over time these values became greater for the drier clear‐cuts. The mature forests showed no change in native species abundance in response to invasion. Clear‐cut‐drier stands showed a decrease, while the more mesic stands showed an increase in native plant richness, diversity and abundance in response to invasion. The drier clear‐cuts, with increasing invasions and negative native species impacts, were indicative of the back‐seat driver model. The hitchhiker model, a new term, described increasing plant invasions with no measurable impacts.Main ConclusionsThe drier clear‐cut stands exhibit a lack of biotic resistance to invasion, unlike the mesic clear‐cut stands. Increasing invasion in the mature forests suggests that a threshold may be reached that results in impacts on the native vegetation, but with no increase in native plant abundance to help alleviate these effects.
Cerebral effects of glucagon‐like peptide‐1 receptor blockade before and after Roux‐en‐Y gastric bypass surgery in obese women: A proof‐of‐concept resting‐state functional MRI study
Authors: van Duinkerken Eelco , Bernardes Gabriel , van Bloemendaal Liselotte , Veltman Dick J. , Barkhof Frederik , Mograbi Daniel C. , Gerdes Victor E. A. , Deacon Carolyn F. , Holst Jens J. , Drent Madeleine L. , Diamant Michaela , ten Kulve Jennifer , Ijzerman Richard G. 
Published: October 2020

AbstractAimTo assess the effects of Roux‐en‐Y gastric bypass surgery (RYGB)‐related changes in glucagon‐like peptide‐1 (GLP‐1) on cerebral resting‐state functioning in obese women.Materials and MethodsIn nine obese females aged 40‐54 years in the fasted state, we studied the effects of RYGB and GLP‐1 on five a priori selected networks implicated in food‐ and reward‐related processes as well as environment monitoring (default mode, right frontoparietal, basal ganglia, insula/anterior cingulate and anterior cingulate/orbitofrontal networks).ResultsBefore surgery, GLP‐1 receptor blockade (using exendin9‐39) was associated with increased right caudate nucleus (basal ganglia network) and decreased right middle frontal (right frontoparietal network) connectivity compared with placebo. RYGB resulted in decreased right orbitofrontal (insula/anterior cingulate network) connectivity. In the default mode network, after surgery, GLP‐1 receptor blockade had a larger effect on connectivity in this region than GLP‐1 receptor blockade before RYGB (all PFWE < .05). Results remained similar after correction for changes in body weight. Default mode and right frontoparietal network connectivity changes were related to changes in body mass index and food scores after RYGB.ConclusionsThese findings suggest GLP‐1 involvement in resting‐state networks related to food and reward processes and monitoring of the internal and external environment, pointing to a potential role for GLP‐1–induced changes in resting‐state connectivity in RYGB‐mediated weight loss and appetite control.