bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determination of vancomycin exposure target and individualised dosing recommendations for neonates: model-informed precision dosing
Authors: Tang Zhe , Guan Jing , Li Jingjing , Yu Yanxia , Qian Miao , Cao Jiang , Shuai Weiwei , Jiao Zheng 
Published: April 2020

AbstractFew studies incorporating population pharmacokinetic/pharmacodynamic (Pop-PK/PD) modelling have been conducted to quantify the exposure target of vancomycin in neonates. To determine this target and dosing recommendations, a retrospective observational cohort study was established in neonates (chictr.org.cn, ChiCTR1900027919). A Pop-PK model was developed to estimate PK parameters. Causalities between acute kidney injury (AKI) occurrence and vancomycin use were verified using Naranjo criteria. Thresholds of vancomycin exposure in predicting AKI or efficacy were identified via classification and regression tree analysis. Associations between exposure thresholds and clinical outcomes including AKI and efficacy, were analysed by logistic regression. Dosing recommendations were designed using Monte Carlo (MC) simulations based on the optimised exposure target. Pop-PK modelling included 182 neonates with 411 observations. In covariate analysis, neonatal physiological maturation, renal function, and concomitant use of vasoactive drugs (VAS) significantly affected vancomycin pharmacokinetics. Seven cases of vancomycin-induced AKI were detected. Area under the concentration–time curve from 0–24 h (AUC0-24) ≥ 485 mg·h/L was an independent risk factor for AKI after adjusting for VAS co-administration. Clinical efficacy of vancomycin was analysed in 42 patients with blood culture-proven staphylococcal sepsis. AUC0–24to minimum inhibitory concentration (AUC0–24/MIC) ≥ 234 was the only significant predictor of clinical effectiveness. MC simulations indicated that regimens in Neonatal Formulary 7 and Red Book (2018) were not suitable for all neonates. In summary, AUC0-24of 240-480 assuming MIC = 1 mg/L is a recommended exposure target of vancomycin in neonates. Model-informed dosing regimens are valuable in clinical practice.HighlightsThe optimised neonatal exposure target of vancomycin was uniquely quantifiedDay 1 exposure of vancomycin is the predictor for clinical outcomes in neonatesVancomycin-induced acute kidney injury is not related to high exposure aloneA lower exposure target is likely to be more effective for neonates than for adultsMonte Carlo simulation provides a more suitable dosing regimen for neonates
Why is chest CT important for early diagnosis of COVID-19? Prevalence matters
Authors: Esposito Antonio , Palmisano Anna , Scotti Giulia Maria , Morelli Marco J. , Vignale Davide , De Cobelli Francesco , Tonon Giovanni , Tacchetti Carlo 
Published: April 2020

AbstractSARS-CoV-2 viral infection is a global pandemic disease (COVID-19). Reaching a swift, reliable diagnosis of COVID-19 in the emergency departments is imperative to direct patients to proper care and to prevent disease dissemination. COVID-19 diagnosis is based on the identification of viral RNA through RT-PCR from oral-nasopharyngeal swabs, which however presents suboptimal sensitivity and may require several hours in overstressed laboratories. These drawbacks have called for an additional, complementary first line approach. CT is the gold standard method for the detection of interstitial pneumonia, a hallmark feature of COVID-19, often present in the asymptomatic stage of the disease. Here, we show that CT scan presents a sensitivity of 95.48% (std.err=0.35%), vastly outperforming RT-PCR. Additionally, as diagnostic accuracy is influenced by disease prevalence, we argue that predictive values provide a more precise measure of CT reliability in the current pandemics. We generated a model showing that CT scan is endowed with a high negative predictive value (> 90%) and positive predictive value (69 - 84%), for the range of prevalence seen in countries with rampant dissemination. We conclude that CT is an expedite and reliable diagnostic tool to support first line triage of suspect COVID-19 patients in areas where the diffusion of the virus is widespread.
Development of an in vitro senescent hepatic cell model for metabolic studies in aging
Authors: Singh Brijesh Kumar , Tripathi Madhulika , Sandireddy Reddemma , Tikno Keziah , Zhou Jin , Yen Paul Michael 
Published: April 2020

AbstractAlthough aging in the liver contributes to the development of chronic liver diseases such as NAFLD and insulin resistance, little known about the molecular and metabolic details of aging in hepatic cells. To examine these issues, we used sequential oxidative stress with hydrogen peroxide to induce premature senescence in AML12 hepatic cells. The senescent cells exhibited molecular and metabolic signatures, increased SA-βGal and γH2A.X staining, and elevated senescence and pro-inflammatory gene expression that resembled livers from aged mice. Metabolic phenotyping showed fuel switching towards glycolysis and mitochondrial glutamine oxidation as well as impaired energy production. The senescent AML12 cells also had increased mTOR signaling and decreased autophagy which likely contributed to the fuel switching from β-oxidation that occurred in normal AML12 cells. Additionally, senescence activated secretory proteins from conditioned media of senescent cells sensitized normal AML12 cells to palmitate-induced toxicity, a known pathological effect of hepatic aging. In summary, we have generated senescent AML12 cells which displayed the molecular hallmarks of aging, and also exhibited the aberrant metabolic phenotype, mitochondrial function, and cell signaling that occur in the aged liver.
SMN1copy-number and sequence variant analysis from next generation sequencing data
Authors: Lopez-Lopez Daniel , Loucera Carlos , Carmona Rosario , Aquino Virginia , Salgado Josefa , Pasalodos Sara , Miranda María , Alonso Ángel , Dopazo Joaquín 
Published: April 2020

AbstractSpinal Muscular Atrophy (SMA) is a severe neuromuscular autosomal recessive disorder affecting 1/10,000 live births. Most SMA patients present homozygous deletion ofSMN1, while the vast majority of SMA carriers present only a singleSMN1copy. The sequence similarity betweenSMN1andSMN2, and the complexity of the SMN locus makes the estimation of the SMN1 copy-number by next generation sequencing (NGS) very difficult Here, we present SMAca, the first python tool to detect SMA carriers and estimate the absolute SMN1 copy-number using NGS data. Moreover, SMAca takes advantage of the knowledge of certain variants specific toSMN1duplication to also identify silent carriers. This tool has been validated with a cohort of 326 samples from the Navarra 1000 Genomes project (NAGEN1000). SMAca was developed with a focus on execution speed and easy installation. This combination makes it especially suitable to be integrated into production NGS pipelines. Source code and documentation are available on Github at:www.github.com/babelomics/SMAca
Evolutionary patterns of 64 vertebrate genomes (species) revealed by phylogenomics analysis of protein-coding gene families
Authors: Song Jia , Han Xia , Lin Kui 
Published: April 2020

AbstractBackgroundRecent studies have demonstrated that phylogenomics is an important basis for answering many fundamental evolutionary questions. With more high-quality whole genome sequences published, more efficient phylogenomics analysis workflows are required urgently.ResultsTo this end and in order to capture putative differences among evolutionary histories of gene families and species, we developed a phylogenomics workflow for gene family classification, gene family tree inference, species tree inference and duplication/loss events dating. Our analysis framework is on the basis of two guiding ideas: 1) gene trees tend to be different from species trees but they influence each other in evolution; 2) different gene families have undergone different evolutionary mechanisms. It has been applied to the genomic data from 64 vertebrates and 5 out-group species. And the results showed high accuracy on species tree inference and few false-positives in duplication events dating.ConclusionsBased on the inferred gene duplication and loss event, only 9∼16% gene families have duplication retention after a whole genome duplication (WGD) event. A large part of these families have ohnologs from two or three WGDs. Consistent with the previous study results, the gene function of these families are mainly involved in nervous system and signal transduction related biological processes. Specifically, we found that the gene families with ohnologs from the teleost-specific (TS) WGD are enriched in fat metabolism, this result implyng that the retention of such ohnologs might be associated with the environmental status of high concentration of oxygen during that period.
Measuring ontogenetic shifts in central-place foraging insects: a case study with honey bees
Authors: Requier Fabrice , Henry Mickaël , Decourtye Axel , Brun François , Aupinel Pierrick , Rebaudo François , Bretagnolle Vincent 
Published: April 2020

AbstractMeasuring time-activity budgets over the complete individual lifespan is now possible for many animals with the recent advances of life-long individual monitoring devices. Although analyses of changes in the patterns of time-activity budgets have revealed ontogenetic shifts in birds or mammals, no such technique has been applied to date on insects.We tested an automated breakpoint-based procedure to detect, assess and quantify shifts in the temporal pattern of the flight activities in honey bees. We assumed that the learning and foraging stages of honey bees will differ in several respects, to detect the age at onset of foraging (AOF).Using an extensive dataset covering the life-long monitoring of 2,100 individuals, we compared the AOF outputs with the more conventional approaches based on arbitrary thresholds. We further evaluated the robustness of the different methods comparing the foraging time-activity budget allocations between the presumed foragers and confirmed foragers.We revealed a clear-cut learning-foraging ontogenetic shift that differs in duration, frequency, and time of occurrence of flights. Although AOF appeared to be highly plastic among bees, the breakpoint-based procedure seems better able to detect it than arbitrary threshold-based methods that are unable to deal with inter-individual variation.We developed theaofR-package including a broad range of examples with both simulated and empirical dataset to illustrate the simplicity of use of the procedure. This simple procedure is generic enough to be derived from any individual life-long monitoring devices recording the time-activity budgets of honey bees, and could propose new ecological applications of bio-logging to detect ontogenetic shifts in the behaviour of central-place foraging insects.
Measuring robust functional connectivity from resting-state MEG using amplitude and entropy correlation across frequency-bands and temporal scales
Authors: Godfrey Megan , Singh Krish D. 
Published: April 2020

AbstractRecent studies have shown how MEG can reveal spatial patterns of functional connectivity using frequency-specific oscillatory coupling measures and that these may be modified in disease. However, there is a need to understand both how repeatable these patterns are across participants and how these measures relate to the moment-to-moment variability (or ‘irregularity’) of neural activity seen in healthy brain function. In this study, we used Multi-scale Rank-Vector Entropy (MRVE) to calculate the dynamic timecourses of signal variability over a range of temporal scales. The correlation of MRVE timecourses was then used to detect functional connections in resting state MEG recordings that were robust over 183 participants and varied with temporal scale. We then compared these MRVE connectivity patterns to those derived using more standard amplitude-amplitude coupling measures, using methods designed to quantify the consistency of these patterns across participants.Using oscillatory amplitude envelope correlation (AEC), the most consistent connectivity patterns, across the cohort, were seen in the alpha and beta frequency bands. At fine temporal scales (corresponding to ‘scale frequencies’, fS = 30-150Hz), MRVE correlation detected mostly occipital and parietal connections and these showed high similarity with the networks identified by AEC in the alpha and beta frequency bands. The most consistent connectivity profiles between participants were given by MRVE correlation at fS = 75Hz and AEC in the beta band.It was also found that average mid-to fine scale variability within each region (fS ∼ 10-150Hz) negatively correlated with the region’s overall connectivity strength with other brain areas, as measured by fine scale MRVE correlation (fS ∼ 30-150Hz) and by alpha and beta band AEC. These findings suggest that local activity at frequencies fS ≳ 10Hz becomes more regular when a region exhibits high levels of resting state connectivity.
The common analgesic paracetamol enhances the anti-tumour activity of decitabine through exacerbation of oxidative stress
Authors: Gleneadie Hannah J. , Baker Amy H. , Batis Nikolaos , Bryant Jennifer , Jiang Yao , Clokie Samuel J.H. , Mehanna Hisham , Garcia Paloma , Gendoo Deena M.A. , Roberts Sally , Molinolo Alfredo A. , Gutkind J. Silvio , Scheven Ben A. , Cooper Paul R. , Khanim Farhat L. , Wiench Malgorzata 
Published: April 2020

AbstractThe DNA demethylating agent 5-aza-2’-deoxycytidine (DAC, decitabine) has anti-cancer therapeutic potential, but its clinical efficacy is hindered by DNA damage-related side effects. Here we describe how paracetamol augments the effects of DAC on cancer cell proliferation and differentiation, without enhancing DNA damage. Firstly, DAC specifically upregulates cyclooxygenase-2-prostaglandin E2pathway, inadvertently increasing cancer cell survival, while the addition of paracetamol offsets this effect. Secondly, combined treatment leads to glutathione depletion and ROS accumulation with oxidative stress further enhanced by DAC suppressing anti-oxidant and thioredoxin responses. The benefits of combined treatment are demonstrated here in head and neck squamous cell carcinoma (HNSCC) and acute myeloid leukaemia cell lines, further corroborated in a HNSCC xenograft mouse model and through mining of publicly available DAC and paracetamol responses. In summary, the addition of paracetamol could allow for DAC dose reduction, widening its clinical usability and providing a strong rationale for consideration in cancer therapy.
PHARMACOLOGICAL PROTEIN INACTIVATION BY TARGETING FOLDING INTERMEDIATES
Authors: Spagnolli Giovanni , Massignan Tania , Astolfi Andrea , Biggi Silvia , Brunelli Paolo , Libergoli Michela , Ianeselli Alan , Orioli Simone , Boldrini Alberto , Terruzzi Luca , Maietta Giulia , Rigoli Marta , Lorenzo Nuria Lopez , Fernandez Leticia C. , Tosatto Laura , Linsenmeier Luise , Vignoli Beatrice , Petris Gianluca , Gasparotto Dino , Pennuto Maria , Guella Graziano , Canossa Marco , Altmeppen Hermann Clemens , Lolli Graziano , Biressi Stefano , Pastor Manuel Martin , Requena Jesús R. , Mancini Ines , Barreca Maria Letizia , Faccioli Pietro , Biasini Emiliano 
Published: April 2020

ABSTRACTRecent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. Using these techniques to study the negative regulation of the androgen receptor (AR), we discovered a key functional role played by non-native metastable states appearing along the folding pathway of this protein. This unexpected observation inspired us to design a completely novel drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein expression by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP, and identified four different small molecule ligands for this conformer, all capable of selectively lowering the expression of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression.
Equine Facial Action Coding System for determination of pain-related facial responses in videos of horses
Authors: Rashid Maheen , Silventoinen Alina , Gleerup Karina B. , Andersen Pia H. 
Published: April 2020

1AbstractDuring the last decade, pain scales including facial expressions as indicators of pain have been developed for horses, mostly relying on direct observations or inspection of images. Despite differences in the research conditions and methodology the different scales focus on the same regions of the face, corresponding to moveable facial muscles related to the ears, eyes, nostrils, lips and chin. However, a detailed comparison of the facial activities occurring during pain is not possible. We used a Facial Action Coding System modified for horses to code and analyse video recordings from an earlier study of acute short-term experimental pain and from clinical cases with and without pain. We demonstrated for the first time EquiFACS based changes to pain in video of horses, using traditional statistical methods based on frequency, and novel analyses based on sliding observation windows and co-occurrence of facial actions. The most prominent differences of the experimental horses were related to the lower face actionschin raiserandnostril dilator, while less prominent, but significantly more frequent actions were related to the eye region,inner brow raiser(AU101),increased eye white(AD1),half blink(AU47), andear rotator(EAD104).Ears forward(EAD101) andeye blink(AU145) were not associated to pain. Based on this we selected the two lower face actions for analysis of the clinical videos, and found that their co-occurrence within a window of 10 to 15 second gave 100% positive predictive values, as compared to the rating from three expert pain raters. Using our developed co-occurrence analyses we were surprised to detect that the chance of identifying three or more of the facial actions related to pain in 0.04 second sequence, corresponding to one frame, was below 3%, indicating that use of randomly selected images for pain scoring may be a very insensitive method.
Screening anti-infectious molecules againstMycobacterium ulcerans: a step towards decontaminating environmental specimens
Authors: Hammoudi N , Verdot R , Delorme J , Bouam A , Drancourt M 
Published: April 2020

AbstractMycobacterium ulcerans, a non-tuberculous mycobacterium responsible for Buruli ulcer, is residing in poorly defined environmental niches in the vicinity of stagnant water points where very few isolates have been confirmed. In the perspective of culturingM. ulceransfrom such contaminated environmental specimens, we tested thein vitrosusceptibility ofM. ulceransCU001 strain co-cultivated with XTC cells to anti-infectious molecules registered in the French pharmacopoeia, using a standardised concentration, to find-out molecules inactive againstM. ulceranswhich could be incorporated in decontaminating solution. Of 116 tested molecules, 64 (55.1%] molecules including 34 (29.3%] antibiotics, 14 (12%] antivirals, 8 (6.8%] antiparasitic and 8 (6.8%] antifungals were ineffective againstM. ulceransCU001; leaving 52 molecules active againstM. ulceransCU001. Three such inactive antimicrobial molecules (oxytetracycline, polymyxin E and voriconazole] were then selected to make a decontamination solution shown to respectM. ulceransCU001 viability. These three antimicrobials could be incorporated into a decontamination solution for the tentative isolation and culture ofM. ulceransfrom environmental samples.
Mucin glycans signal through the sensor kinase RetS to inhibit virulence-associated traits inPseudomonas aeruginosa
Authors: Wang Benjamin X. , Wheeler Kelsey M. , Cady Kyle C. , Lehoux Sylvain , Cummings Richard D. , Laub Michael T. , Ribbeck Katharina 
Published: April 2020

AbstractMucus is a densely populated ecological niche that coats all epithelia, and plays a critical role in protecting the human body from infections. Although traditionally viewed as a physical barrier, emerging evidence suggests that mucus can directly suppress virulence traits in opportunistic pathogens likePseudomonas aeruginosa. However, the molecular mechanisms by which mucus affords this protection are unclear. Here, we show that mucins, and particularly their associated glycans, activate the sensor kinase RetS via its Dismed2 domain inP. aeruginosa. We find that this RetS-dependent signaling leads to the direct inhibition of the GacS-GacA two-component system, the activity of which is associated with a chronic infection state. This signaling includes the downregulation of the type VI secretion system (T6SS), and prevents T6SS-dependent bacterial killing byP. aeruginosa. Overall, these results shed light on how mucus impactsP. aeruginosabehavior in the human host, and may inspire novel approaches for controllingP. aeruginosainfections.
Highly efficient multiplex editing: One-shot generation of 8xNicotiana benthamianaand 12x Arabidopsis mutants
Authors: Stuttmann Johannes , Barthel Karen , Martin Patrick , Ordon Jana , Erickson Jessica L. , Herr Rosalie , Ferik Filiz , Kretschmer Carola , Berner Thomas , Keilwagen Jens , Marillonnet Sylvestre , Bonas Ulla 
Published: April 2020

SummaryGenome editing by RNA-guided nucleases, such asSpCas9, has been used in numerous different plant species. However, to what extent multiple independent loci can be targeted simultaneously by multiplexing has not been well-documented. Here, we developed a toolkit, based on a highly intron-optimized zCas9i gene, which allows assembly of nuclease constructs expressing up to 32 sgRNAs. We used this toolkit to explore the limits of multiplexing in two major model species, and report on isolation of transgene-free octupleNicotiana benthamianaand duodecuple (12x)Arabidopsis thalianamutant lines in a single generation (T1and T2, respectively). We developed novel counter-selection markers forN. benthamiana, most importantlySl-FAST2, comparable to the well-established Arabidopsis seed fluorescence marker, and FCY-UPP, based on production of toxic 5-fluorouracyl in presence of a precursor. Targeting eight genes with an array of nine different sgRNAs and relying on FCY-UPP for selection of non-transgenic T1, we identifiedN. benthamianamutant lines with astonishingly high efficiencies: All analyzed plants carried mutations in all genes (~112/116 target sites edited). Furthermore, we targeted 12 genes by an array of 24 sgRNAs inA. thaliana. Efficiency was significantly lower inA. thaliana, and our results indicate Cas9 availability is the limiting factor in such higher order multiplexing applications. We identify a duodecuple mutant line by a combination of phenotypic screening and amplicon sequencing. The resources and results presented provide new perspectives for how multiplexing can be used to generate complex genotypes or to functionally interrogate groups of candidate genes.