bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histogram-based models on non-thin section chest CT predict invasiveness of primary lung adenocarcinoma subsolid nodules
Authors: Oikonomou Anastasia , Salazar Pascal , Zhang Yuchen , Hwang David M. , Petersen Alexander , Dmytriw Adam A. , Paul Narinder S. , Nguyen Elsie T. 
Published: April 2019

Abstract109 pathologically proven subsolid nodules (SSN) were segmented by 2 readers on non-thin section chest CT with a lung nodule analysis software followed by extraction of CT attenuation histogram and geometric features. Functional data analysis of histograms provided data driven features (FPC1,2,3) used in further model building. Nodules were classified as pre-invasive (P1, atypical adenomatous hyperplasia and adenocarcinoma in situ), minimally invasive (P2) and invasive adenocarcinomas (P3). P1 and P2 were grouped together (T1) versus P3 (T2). Various combinations of features were compared in predictive models for binary nodule classification (T1/T2), using multiple logistic regression and non-linear classifiers. Area under ROC curve (AUC) was used as diagnostic performance criteria. Inter-reader variability was assessed using Cohen’s Kappa and intra-class coefficient (ICC). Three models predicting invasiveness of SSN were selected based on AUC. First model included 87.5 percentile of CT lesion attenuation (Q.875), interquartile range (IQR), volume and maximum/minimum diameter ratio (AUC:0.89, 95%CI:[0.75 1]). Second model included FPC1, volume and diameter ratio (AUC:0.91, 95%CI:[0.77 1]). Third model included FPC1, FPC2 and volume (AUC:0.89, 95%CI:[0.73 1]). Inter-reader variability was excellent (Kappa:0.95, ICC:0.98). Parsimonious models using histogram and geometric features differentiated invasive from minimally invasive/pre-invasive SSN with good predictive performance in non-thin section CT.
Intergeneric hybrids inform reproductive isolating barriers in the Antarctic icefish radiation
Authors: Desvignes Thomas , Le François Nathalie R. , Goetz Laura C. , Smith Sierra S. , Shusdock Kathleen A. , Parker Sandra K. , Postlethwait John H. , Detrich H. William 
Published: April 2019

AbstractInterspecific hybridization or barriers to hybridization may have contributed to the diversification of Antarctic icefishes (Channichthyidae), but data supporting these hypotheses is scarce. To understand the potential for hybridization and to investigate reproductive isolating mechanisms among icefish species, we performedin vitrofertilization experiments using eggs from a female blackfin icefishChaenocephalus aceratusand sperm from a male of another genera, the ocellated icefishChionodraco rastrospinosus. Sequencing of genomic and mitochondrial DNA confirmed the intergeneric hybrid nature of resulting embryos which successfully developed and hatched as active larvae at about four and a half months during the Antarctic winter. This result demonstrates the compatibility of gametes of these two species and the viability of resulting zygotes and larvae. Due to logistic constraints and the slow developmental rate of icefishes, we could not test for long-term hybrid viability, fertility, fitness, or hybrid breakdown. Analysis of our fishing records and available literature, however, suggests that the strongest barriers to hybridization among parapatric icefish species are likely to be behavioral and characterized by assortative mating and species-specific courtship and nesting behaviors. This conclusion suggests that, in long-lived fish species with late sexual maturity and high energetic investment in reproduction like icefishes, pre-mating barriers are energetically more efficient than post-mating barriers to prevent hybridization.
Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid
Authors: Kakuda Keita , Ikenaka Kensuke , Araki Katsuya , So Masatomo , Aguirre César , Kajiyama Yuta , Konaka Kuni , Noi Kentaro , Baba Kousuke , Tsuda Hiroshi , Nagano Seiichi , Ohmichi Takuma , Nagai Yoshitaka , Tokuda Takahiko , El-Agnaf Omar M. A. , Ogi Hirotsugu , Goto Yuji , Mochizuki Hideki 
Published: April 2019

Abstractα-Synuclein aggregates, a key hallmark of the pathogenesis of Parkinson’s disease, can be amplified by using their seeding activity, and the evaluation of the seeding activity of cerebrospinal fluid (CSF) is reportedly useful for diagnosis. However, conventional shaking-based assays are time-consuming procedures, and the clinical significance of the diversity of seeding activity among patients remains to be clarified. Previously, we reported a high-throughput ultrasonication-induced amyloid fibrillation assay. Here, we adapted this assay to amplify and detect α-synuclein aggregates from CSF, and investigated the correlation between seeding activity and clinical indicators. We confirmed that this assay could detect α-synuclein aggregates prepared in vitro and also aggregates released from cultured cells. The seeding activity of CSF correlated with the levels of α-synuclein oligomers measured by an enzyme-linked immunosorbent assay. Moreover, the seeding activity of CSF from patients with Parkinson’s disease was higher than that of control patients. Notably, the lag time of patients with Parkinson’s disease was significantly correlated with the MIBG heart-to-mediastinum ratio. These findings showed that our ultrasonication-based assay can rapidly amplify misfolded α-synuclein and can evaluate the seeding activity of CSF.
Developmental differences in the expression of ABC transporters at rat brain barrier interfaces following chronic exposure to diallyl sulfide
Authors: Koehn Liam M. , Dziegielewska Katarzyna M. , Møllgård Kjeld , Saudrais Elodie , Strazielle Nathalie , Ghersi-Egea Jean-Francois , Saunders Norman R. , Habgood Mark D. 
Published: April 2019

AbstractMany pregnant women and prematurely born infants require medication for clinical conditions including cancer, cardiac defects and psychiatric disorders. In adults drug transfer from blood into brain is mostly restricted by efflux mechanisms (ATP-binding cassette, ABC transporters). These mechanisms have been little studied during brain development. Here expression of eight ABC transporters (abcb1a, abcb1b, abcg2, abcc1, abcc2, abcc3, abcc4, abcc5) and activity of conjugating enzyme glutathione-s-transferase (GST) were measured in livers, brain cortices (blood-brain-barrier) and choroid plexuses (blood-cerebrospinal fluid, CSF, barrier) during postnatal rat development. Controls were compared to animals chronically injected (4 days, 200 mg/kg/day) with known abcb1a inducer diallyl sulfide (DAS). Results reveal both tissue- and age-dependent regulation. In liver abcb1a and abcc3 were up-regulated at all ages. In cortex abcb1a/b, abcg2 and abcc4/abcc5 were up-regulated in adults only, while in choroid plexus abcb1a and abcc2 were up-regulated only at P14. DAS treatment increased GST activity in livers, but not in cortex or choroid plexuses. Immunocytochemistry of ABC transporters at the CSF-brain interface showed that PGP and BCRP predominated in neuroepithelium while MRP2/4/5 were prominent in adult ependyma. These results indicate an age-related capacity of brain barriers to dynamically regulate their defence mechanisms when chronically challenged by xenobiotic compounds.
Structural bases of peptidoglycan recognition by lysostaphin SH3b domain
Authors: Mitkowski Paweł , Jagielska Elżbieta , Nowak Elżbieta , Bujnicki Janusz M. , Stefaniak Filip , Niedziałek Dorota , Bochtler Matthias , Sabała Izabela 
Published: April 2019

AbstractStaphylococcus simulans lysostaphin cleaves pentaglycine cross-bridges between stem peptides in the peptidoglycan of susceptible staphylococci, including S. aureus. This enzyme consists of an N-terminal catalytic domain and a cell wall binding domain (SH3b), which anchors the protein to peptidoglycan. Although structures of SH3bs from lysostaphin are available, the binding modes of peptidoglycan to these domains are still unclear. We have solved the crystal structure of the lysostaphin SH3b domain in complex with a pentaglycine peptide representing the peptidoglycan cross-bridge. The structure identifies a groove between β1 and β2 strands as the pentaglycine binding site. The structure suggests that pentaglycine specificity of the SH3b arises partially directly by steric exclusion of Cβ atoms in the ligand and partially indirectly due to the selection of main chain conformations that are easily accessible for glycine, but not other amino acid residues. We have revealed further interactions of SH3b with the stem peptides with the support of bioinformatics tools. Based on the structural data we have attempted engineering of the domain specificity and have investigated the relevance of the introduced substitutions on the domain binding and specificity, also in the contexts of the mature lysostaphin and of its bacteriolytic activity.
Relation between Baseline Total Serum Cortisol Level and Outcome in Pediatric Intensive Care Unit
Authors: Bekhit Osama E. , Mohamed Shereen A. , Yousef Remon M. , AbdelRasol Hoiyda A. , Khalaf Nirvana A. , Salah Fatma 
Published: April 2019

AbstractElevated cortisol level is an component of the stress response. However, some patients have low cortisol levels; a condition termed: critical illness-related corticosteroid insufficiency (CIRCI). Basal cortisol levels during PICU admission may be related to outcome. This prospective cohort study aimed to assess basal total serum cortisol levels and their relation to outcome in PICU. The study included 81 children over 6 months. Total serum cortisol was assessed using an early morning sample. The severity of illness was assessed using the PRISM-III score. Outcome measures included mechanical ventilation duration, use of inotropic support, length of stay, mortality. Comparison between patients’ subgroups according to total serum cortisol levels revealed significantly higher PRISM-III score in patients with total serum cortisol levels. In addition, those patients had a significantly higher mortality rate when compared with patients with low and normal total serum cortisol levels. Multivariate logistic regression analysis recognized high total serum cortisol level and PRISM-III score as significant predictors of mortality. We concluded that PRISM-III score and elevated total serum cortisol levels are significant predictors of mortality in the PICU. Although CIRCI is prevalent in this population, it wasn’t associated with an increased mortality rate.
Intrinsic molecular insights to enhancement of biogas production from kitchen refuse using alkaline-microwave pretreatment
Authors: Singh Puneet Kumar , Verma Suresh K. , Ojha Sanjay Kumar , Panda Pritam Kumar , Srichandan Haragobinda , Jha Ealisha , Mishra Snehasish 
Published: April 2019

AbstractThe current study analyzed and optimized the concentration of NaOH for alkaline pretreatment of kitchen refuse for biogas production. Also, the benefits of microwave assistance in enhanced biogasification of kitchen refuse were evaluated. The TS, VS and structural changes were compared using standard experimental techniques. Molecular dynamics was investigated for the molecular level changes leading to higher biogasification in NaOHmicrowave combined pretreatment. The methane and biogas yields were calculated to validate the benefits of microwave assistance in efficient biogasification. The NaOH-microwave combined pretreatment showed higher VS production. Microwave treatment degraded and removed lignin more efficiently. Molecular dynamics studies revealed the induction of configurational instability in lignin and cellulose molecules with variable temperatures. The methane and biogas production increased with 6% NaOH concentration, and decreased at higher NaOH concentration till 10%. Microwave assistance declined the required NaOH concentration further to 4%. Thus, as compared to 6% NaOH concentration required for an efficient pretreatment, the kitchen refuse was efficiently pretreated with 4% NaOH concentration when combined with a 30 min duration microwaving. The experimental and computational data provided a detailed analysis proposing an optimized, novel and promising method to pretreat kitchen refuse for efficient and enhanced biogas production.
An in vivo wound healing model for the characterization of the angiogenic process and its modulation by pharmacological interventions
Authors: Schneider Martin Karl , Ioanas Horea-Ioan , Xandry Jael , Rudin Markus 
Published: April 2019

AbstractAngiogenesis during wound healing is essential for tissue repair and also affected during cancer treatment by anti-angiogenic drugs. Here, we introduce a minimally invasive wound healing model in the mouse ear to assess angiogenesis with high spatiotemporal resolution in a longitudinal manner in vivo using two-photon microscopy in mice expressing GCaMP2 in arterial endothelial cells. The development of vascular sprouts occurred in a highly orchestrated manner within a time window of 8 days following wounding. Novel sprouts developed exclusively from the distal stump of the transsected arteries, growing towards the proximal arterial stump. This was in line with the incidence of Ca2+ transients in the arterial endothelial cells, most probably a result of VEGF stimulation, which were more numerous on the distal part. Functional analysis revealed perfusion across the wound site via arterial sprouts developed between days 6 and 8 following the incision. At day 8, proximal and distal arteries were structurally and functionally connected, though only 2/3 of all sprouts detected were actually perfused. Treatment with the FDA approved drug, sunitinib, the preclinical drug AZD4547, as well as with the combination of the two agents had significant effects on both structural and functional readouts of neo-angiogenesis. The simplicity and high reproducibility of the model makes it an attractive tool for elucidating migratory activity, phenotype and functionality of endothelial cells during angiogenesis and for evaluating specific anti-angiogenic drug interventions.
Tuning of mRNA stability through altering 3′-UTR sequences generates distinct output expression in a synthetic circuit driven by p53 oscillations
Authors: Koh Woo Seuk , Porter Joshua R. , Batchelor Eric 
Published: April 2019

AbstractSynthetic biological circuits that can generate outputs with distinct expression dynamics are useful for a variety of biomedical and industrial applications. We present a method to control output dynamics by altering output mRNA decay rates. Using oscillatory expression of the transcription factor p53 as the circuit regulator, we use two approaches for controlling target gene transcript degradation rates based on the output gene’s 3′-untranslated region (3′-UTR): introduction of copies of destabilizing AU-rich elements into the 3′-UTR or swapping in naturally occurring 3′-UTRs conferring different transcript stabilities. As a proof of principle, we apply both methods to control the expression dynamics of a fluorescent protein and visualize the circuit output dynamics in single living cells. We then use the naturally occurring 3′-UTR approach to restore apoptosis in a tunable manner in a cancer cell line deficient for caspase-3 expression. Our method can be readily adapted to regulate multiple outputs each with different expression dynamics under the control of a single naturally occurring or synthetically constructed biological oscillator.
The molecular genetics of hand preference revisited
Authors: de Kovel Carolien G. F. , Francks Clyde 
Published: April 2019

AbstractHand preference is a prominent behavioural trait linked to human brain asymmetry. A handful of genetic variants have been reported to associate with hand preference or quantitative measures related to it. Most of these reports were on the basis of limited sample sizes, by current standards for genetic analysis of complex traits. Here we performed a genome-wide association analysis of hand preference in the large, population-based UK Biobank cohort (N = 331,037). We used gene-set enrichment analysis to investigate whether genes involved in visceral asymmetry are particularly relevant to hand preference, following one previous report. We found no evidence supporting any of the previously suggested variants or genes, nor that genes involved in visceral laterality have a role in hand preference. It remains possible that some of the previously reported genes or pathways are relevant to hand preference as assessed in other ways, or else are relevant within specific disorder populations. However, some or all of the earlier findings are likely to be false positives, and none of them appear relevant to hand preference as defined categorically in the general population. Our analysis did produce a small number of novel, significant associations, including one implicating the microtubule-associated gene MAP2 in handedness.
Optical coherence tomography angiography for noninvasive evaluation of angiogenesis in a limb ischemia mouse model
Authors: Wang Liwei , Chen Zuoguan , Li Yongjun , Yang Jing , Li Yuejie 
Published: April 2019

AbstractWe developed an optical coherence tomography angiography technique by improving the speckle contrast algorithm and the imaging process. This technique, which can achieve angiogenesis imaging in vivo without increasing trauma, was used to evaluate the microvasculature in limb ischemia mice. Sixteen left hindlimb ischemia mice were randomly allocated into CuSO4 and saline groups. Within 7 days after treatment, limb ischemic damage, temperature and histological staining were assessed by traditional methods. In addition, angiogenesis was evaluated using an optical coherence tomography angiography system in vivo. All results were compared. After 7 days of treatment, both the ischemic tissue damage score and temperature ratio of the CuSO4 group were significantly higher than those of the control group (all P < 0.05). The number of CD31-positive endothelial cells in the CuSO4 group (0.1836 ± 0.0153) was significantly greater than that in the saline control group (0.0436 ± 0.0069) (P < 0.001). Optical coherence tomography angiography showed that the vessel area density of mice in the CuSO4 group (0.2566 ± 0.0060) was significantly greater than that of mice in the control group (0.2079 ± 0.0202) (P = 0.027). Optical coherence tomography angiography represents a practical and effective method for observing angiogenesis in the mouse hindlimb in vivo without increasing trauma.
HMGB1 is a Central Driver of Dynamic Pro-inflammatory Networks in Pediatric Acute Liver Failure induced by Acetaminophen
Authors: Zamora Ruben , Barclay Derek , Yin Jinling , Alonso Estella M. , Leonis Mike A. , Mi Qi , Billiar Timothy R. , Simmons Richard L. , Squires Robert H. , Vodovotz Yoram 
Published: April 2019

AbstractAcetaminophen (APAP) overdose (APAPo) is predominant in the NIH Pediatric Acute Liver Failure (PALF) Study. We assayed multiple inflammatory mediators in serial serum samples from 13 PALF survivors with APAPo + N-acetylcysteine (NAC, the frontline therapy for APAPo), 8 non-APAPo + NAC, 40 non-APAPo non-NAC, and 12 non-survivors. High Mobility Group Box 1 (HMGB1) was a dominant mediator in dynamic inflammation networks in all sub-groups, associated with a threshold network complexity event at d1–2 following enrollment that was exceeded in non-survivors vs. survivors. We thus hypothesized that differential HMGB1 network connectivity after day 2 is related to the putative threshold event in non-survivors. DyNA showed that HMGB1 is most connected in non-survivors on day 2–3, while no connections were observed in APAPo + NAC and non-APAPo + NAC survivors. Inflammatory dynamic networks, and in particular HMGB1 connectivity, were associated with the use of NAC in the context of APAPo. To recapitulate hepatocyte (HC) damage in vitro, primary C57BL/6 HC and HC-specific HMGB1-null HC were treated with APAP + NAC. Network phenotypes of survivors were recapitulated in C57BL/6 mouse HC and were greatly altered in HMGB1-null HC. HC HMGB1 may thus coordinate a pro-inflammatory program in PALF non-survivors (which is antagonized by NAC), while driving an anti-inflammatory/repair program in survivors.
A molecular biomarker for prediction of clinical outcome in children with ASD, constipation, and intestinal inflammation
Authors: Walker Stephen J. , Langefeld Carl D. , Zimmerman Kip , Schwartz Marshall Z. , Krigsman Arthur 
Published: April 2019

AbstractIn children with autism spectrum disorder (ASD) who present to the gastroenterologist with chronic constipation on a background of colonic inflammation, we have identified two distinct clinical subtypes: (1) patients who experience a sustained state of GI symptomatic remission while on maintenance anti-inflammatory therapy (fast responders) and, (2) those with recurrent right-sided fecal loading requiring regular colon cleanouts during treatment for enterocolitis (slow responders). We hypothesized that a detailed molecular analysis of tissue from the affected region of the colon would provide mechanistic insights regarding the fast versus slow response to anti-inflammatory therapy. To test this, ascending colon biopsy tissues from 35 children with ASD (20 slow responders and 15 fast responders) were analyzed by RNAseq. Hierarchical cluster analysis was performed to assign samples to clusters and gene expression analysis was performed to identify differentially expressed transcripts (DETs) between samples within the clusters. Significant differences were found between the two clusters with fast responder-predominant cluster showing an upregulation of transcripts involved in the activation of immune and inflammatory response and the slow responder-predominant cluster showing significant over-representation of pathways impacting colonic motility (e.g. genes involved in tryptophan and serotonin degradation and mitochondrial dysfunction). Regression analysis identified a single long non-coding RNA that could predict cluster assignment with a high specificity (0.88), sensitivity (0.89) and accuracy (0.89). Comparison of gene expression profiles in the ascending colon from a subset of patients with ASD, chronic right-sided fecal loading constipation and a slow versus fast response to therapy has identified molecular mechanisms that likely contribute to this differential response following the primary therapeutic intervention (i.e. treatment for colonic inflammation with brief induction immunosuppression followed by maintenance non-steroidal anti-inflammatory therapy). Importantly, we have identified a transcript that, if validated, may provide a biomarker that can predict from the outset which patients will be slow responders who would benefit from an alternate therapeutic strategy in treating their constipation.