bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monophosphoryl Lipid a Attenuates Multiorgan Dysfunction During Post-Burn Pseudomonas Aeruginosa Pneumonia in Sheep
Authors: Fukuda Satoshi , Ihara Koji , Bohannon Julia K. , Hernandez Antonio , Patil Naeem K. , Luan Liming , Stothers Cody , Stark Ryan , Prough Donald S. , Herndon David N. , Sherwood Edward R. , Enkhbaatar Perenlei 
Published: May 2019

ABSTRACT

Background:
Monophosphoryl lipid A (MPLA) is a TLR4 agonist that has potent immunomodulatory properties and modulates innate immune function to improve host resistance to infection with common nosocomial pathogens in mice. The goal of this study was to assess the safety and efficacy of MPLA in a sheep model of burn injury and Pseudomonas aeruginosa pneumonia. The sheep provides a favorable model for preclinical testing as their response to TLR4 agonists closely mimics that of humans.

Methods:
Twelve chronically instrumented adult female Merino sheep received 20% total body surface area, third-degree cutaneous burn under anesthesia and analgesia. At 24 h after burn, sheep were randomly allocated to receive: MPLA (2.5 μg/kg i.v., n = 6), or vehicle (i.v., n = 6). At 24 h after MPLA or vehicle treatment, Pseudomonas aeruginosa pneumonia was induced. Sheep were mechanically ventilated, fluid resuscitated and cardiopulmonary variables were monitored for 24 h after induction of pneumonia. Cytokine production, vascular barrier function, and lung bacterial burden were also measured.

Results:
MPLA infusion induced small and transient alterations in core body temperature, heart rate, pulmonary artery pressure, and pulmonary vascular resistance. Pulmonary mechanics were not altered. Vehicle-treated sheep developed severe acute lung injury during Pseudomonas aeruginosa pneumonia, which was attenuated by MPLA as indicated by improved PaO2/FiO2 ratio, oxygenation index, and shunt fraction. Sheep treated with MPLA also exhibited less vascular leak, lower blood lactate levels, and lower modified organ injury score. MPLA treatment attenuated systemic cytokine production and decreased lung bacterial burden.

Conclusions:
MPLA was well tolerated in burned sheep and attenuated development of acute lung injury, lactatemia, cytokinemia, vascular leak, and hemodynamic changes caused by Pseudomonas aeruginosa pneumonia.
Long-Term Selegiline Monotherapy for the Treatment of Early Parkinson Disease
Authors: Mizuno Yoshikuni , Hattori Nobutaka , Kondo Tomoyoshi , Nomoto Masahiro , Origasa Hideki , Takahashi Ryosuke , Yamamoto Mitsutoshi , Yanagisawa Nobuo 
Published: May 2019

Objectives
The aim of this open-label study was to investigate the long-term safety and efficacy of selegiline as monotherapy in Japanese patients with early Parkinson disease (PD).

Methods
We conducted a 56-week prospective study in patients with early PD (N = 134) who had previously completed the randomized, double-blind, placebo-controlled phase III trial of selegiline monotherapy for 12 weeks. In the present study, dosing was titrated from 2.5 to 10 mg/d in increments of 2.5 mg/d for 2 weeks. From the seventh week, the dosage was maintained at 10 mg/d until week 56. The primary outcome was any change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score (part I + II + III) from baseline. Secondary outcomes, including changes in the UPDRS subscores and safety profile, were also evaluated.

Results
Ninety-one (67.9%) patients completed the 56-week study. Treatment with selegiline significantly reduced total UPDRS score from week 4 (mean ± SD, −2.62 ± 3.83; P < 0.0001) to week 56 (−3.39 ± 9.27; P < 0.01). The peak effect was seen at week 20 (−5.79 ± 5.57; P < 0.0001). In addition, we found similar improvements in the UPDRS parts II and III scores. The incidence rate of adverse drug reactions was 44.3% (58 patients) and did not increase during the period of 10 mg selegiline administration.

Conclusions
Long-term monotherapy with selegiline (10 mg/d) was effective and well tolerated in patients with early PD in this 56-week study.
Spurious inference when comparing networks
Authors: Farine Damien R. , Aplin Lucy M. 
Published: May 2019

AbstractComparing networks is challenging. Social networks can be shaped by many factors. Failing to adequately consider non-social processes, including sampling artefacts, can lead to spurious conclusions about differences in social networks among groups. Here we demonstrate that incorrect application of statistical testing methods when comparing networks can generate very high rates of false positives. We then show that null models, specifically pre-network permutation tests, can control for non-social differences in networks and substantially reduce rates of false positives.
A neuromimetic approach to the serial acquisition, long-term storage, and selective utilization of overlapping memory engrams
Authors: Quintanar-Zilinskas Victor 
Published: May 2019

AbstractBiological organisms that sequentially experience multiple environments develop self-organized representations of the stimuli unique to each; moreover, these representations are retained long-term, and sometimes utilize overlapping sets of neurons. This functionality is difficult to replicate in silico for several reasons, such as the tradeoff between stability, which enables retention, and plasticity, which enables ongoing learning. Here, by using a network that leverages an ensemble of neuromimetic mechanisms, I successfully simulate multi-environment learning; additionally, from measurements of synapse states and stimulus recognition performance taken at multiple time points, the following network features emerge as particularly important to its operation. First, while reinforcement-driven stabilization preserves the synapses most important to the representation of each stimulus, pruning eliminates many of the rest, thereby resulting in low-noise representations. Second, in familiar environments, a low baseline rate of exploratory synapse generation balances with pruning to confer plasticity without introducing significant noise; meanwhile, in novel environments, new synapses are reinforced, reinforcement-driven spine generation promotes further exploration, and learning is hastened. Thus, reinforcement-driven spine generation allows the network to temporally separate its pursuit of pruning and plasticity objectives. Third, the permanent synapses interfere with the learning of new environments; but, stimulus competition and long-term depression mitigate this effect; and, even when weakened, the permanent synapses enable the rapid relearning of the representations to which they correspond. This exhibition of memory suppression and rapid recovery is notable because of its biological analogs, and because this biologically-viable strategy for reducing interference would not be favored by artificial objective functions unaccommodating of brief performance lapses. Together, these modeling results advance understanding of intelligent systems by demonstrating the emergence of system-level operations and naturalistic learning outcomes from component-level features, and by showcasing strategies for finessing system design tradeoffs.
Comparative phosphorylation map of Dishevelled3 (DVL3)
Authors: Hanáková Kateřina , Bernatík Ondřej , Ovesná Petra , Kravec Marek , Micka Miroslav , Rádsetoulal Matěj , Potěšil David , Čajánek Lukáš , Zdráhal Zbyněk , Bryja Vítězslav 
Published: May 2019

AbstractIn the presented study we analyze phosphorylation of human Dishevelled 3 (DVL3) induced by its previously reported (CK1ε, NEK2, PLK1, CK2α, RIPK4, PKCδ) and the newly identified (TTBK2, Aurora A) kinases. DVL3 contains 131 Ser/Thr whose phosphorylation generates complex barcodes underlying diverse DVL3 functions in Wnt pathways and other processes. We use quantitative mass spectrometry and via several complementary pipelines calculate site occupancies and quantify phosphorylation of >80 phosphorylated residues. In order to visualize the complex phosphorylation patterns, we design a novel visualization diagram, phosphoplot. Finally, we compare the individual sample and data processing approaches, identify their strengths and weaknesses. Subsequently, we verified a set of anti-phospho-DVL antibodies and were able to successfully confirm induction for several of the phosphorylation sites. From the biological point of view, our data represent an important reference point and a toolbox for further analysis of DVL functions and phosphorylation events that control them.One sentence summaryThe study provides a comprehensive comparison of the phosphorylation of DVL3 induced by eight Ser/Thr kinases and identifies phosphorylation signatures associated with individual kinases.
Deceptive combined effects of short allele dominance and stuttering: an example withIxodes scapularis, the main vector of Lyme disease in the U.S.A.
Authors: De Meeûs Thierry , Chan Cynthia T. , Ludwig John M. , Tsao Jean I. , Patel Jaymin , Bhagatwala Jigar , Beati Lorenza 
Published: May 2019

ABSTRACTNull alleles, short allele dominance (SAD), and stuttering increase the perceived relative inbreeding of individuals and subpopulations as measured by Wright’sFISandFST. Ascertainment bias, due to such amplifying problems are usually caused by inaccurate primer design (if developed from a different species or a distant population), poor DNA quality, low DNA concentration, or a combination of some or all these sources of inaccuracy. When combined, these issues can increase the correlation between polymorphism at concerned loci and, consequently, of linkage disequilibrium (LD) between those. In this note, we studied an original microsatellite data set generated by analyzing nine loci inIxodes scapularisticks from the eastern U.S.A. To detect null alleles and SAD we used correlation methods and variation measures. To detect stuttering, we evaluated heterozygote deficit between alleles displaying a single repeat difference. We demonstrated that an important proportion of loci affected by amplification problems (one with null alleles, two with SAD and three with stuttering) lead to highly significant heterozygote deficits (FIS=0.1,p-value<0.0001). This occurred together with an important proportion (22%) of pairs of loci in significant LD, two of which were still significant after a false discovery rate (FDR) correction, and some variation in the measurement of population subdivision across loci (Wright’sFST). This suggested a strong Wahlund effect and/or selection at several loci. By finding small peaks corresponding to previously disregarded larger alleles in some homozygous profiles for loci with SAD and by pooling alleles close in size for loci with stuttering, we generated an amended dataset. Except for one locus with null alleles and another still displaying a modest SAD, the analyses of the corrected dataset revealed a significant excess of heterozygotes (FIS=-0.07 as expected in dioecious and strongly subdivided populations, with a more reasonable proportion (19%) of pairs of loci characterized by significant LD, none of which stayed significant after the FDR procedure. Strong subdivision was also confirmed by the standardizedFST’ corrected for null alleles (FST’=0.19) and small effective subpopulation sizes (Ne=7).
Structural abnormalities in thalamo-prefrontal tracks revealed by high angular resolution diffusion imaging predict working memory scores in concussed children
Authors: Guberman Guido I. , Houde Jean-Christophe , Ptito Alain , Gagnon Isabelle , Descoteaux Maxime 
Published: May 2019

AbstractBecause of their massive prevalence, wide-ranging sequelae, and insidious nature, concussions are a potentially devastating neurological condition, especially in children. Shearing forces transmitted across the brain during concussions often result in white matter damage. The neuropathological impact of concussions has been discerned from animal studies and includes inflammation, demyelination, and axonal loss. These pathologies can overlap during the subacute stage of recovery. However, due to the challenges of accurately modelling complex white matter structure, these neuropathologies have not yet been differentiated in children in vivo. In the present study, we leveraged recent advances in diffusion imaging modelling, tractography, and tractometry to better understand the neuropathology underlying working memory problems in concussion. Studying a sample of 16 concussed and 46 healthy youths, we used novel tractography methods to isolate 11 working memory tracks. Along these tracks, we measured fractional anisotropy, diffusivities, track volume, apparent fiber density, and free water fraction. In three tracks connecting the right thalamus to the right dorsolateral prefrontal cortex (DLPFC), we found microstructural differences suggestive of myelin alterations. In another track connecting the left anterior-cingulate cortex with the left DLPFC, we found microstructural changes suggestive of axonal loss. Structural differences and tractography reconstructions were reproduced using test-retest analyses. White matter structure in the three thalamo-prefrontal tracks, but not the cingulo-prefrontal track, appeared to play a key role in working memory function. The present results improve understanding of working memory neuropathology in concussions, which constitutes an important first step towards developing neuropathologically-informed biomarkers of concussion in children.
Analysis of distance-based protein structure prediction by deep learning in CASP13
Authors: Xu Jinbo , Wang Sheng 
Published: May 2019

AbstractThis paper reports the CASP13 results of distance-based contact prediction, threading and folding methods implemented in three RaptorX servers, which are built upon the powerful deep convolutional residual neural network (ResNet) method initiated by us for contact prediction in CASP12. On the 32 CASP13 FM (free-modeling) targets with a median MSA (multiple sequence alignment) depth of 36, RaptorX yielded the best contact prediction among 46 groups and almost the best 3D structure modeling among all server groups without time-consuming conformation sampling. In particular, RaptorX achieved top L/5, L/2 and L long-range contact precision of 70%, 58% and 45%, respectively, and predicted correct folds (TMscore>0.5) for 18 of 32 targets. Although on average underperforming AlphaFold in 3D modeling, RaptorX predicted correct folds for all FM targets with >300 residues (T0950-D1, T0969-D1 and T1000-D2) and generated the best 3D models for T0950-D1 and T0969-D1 among all groups. This CASP13 test confirms our previous findings: (1) predicted distance is more useful than contacts for both template-based and free modeling; and (2) structure modeling may be improved by integrating alignment and co-evolutionary information via deep learning. This paper will discuss progress we have made since CASP12, the strength and weakness of our methods, and why deep learning performed much better in CASP13.
ML277 specifically enhances pore opening of KCNQ1 with VSD at the activated state by modulating VSD-pore coupling
Authors: Hou Panpan , Shi Jingyi , White Kelli McFarland , Gao Yuan , Cui Jianmin 
Published: May 2019

AbstractIn response to membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states that correspond to the stepwise activation of the voltage sensing domain (VSD) to the intermediate (I) and activated (A) states. In the heart, KCNQ1 associates with the auxiliary subunit KCNE1 to form the IKs channel that regulates heart rhythm. More than 300 of loss-of-function KCNQ1 mutations cause long QT syndrome (LQTS). KCNE1 suppresses the IO state so that the IKs channel opens only to the AO state. Thus, enhancing AO state presents a potential therapy for anti-LQTS. Here, we systematically tested modulations of KCNQ1 channels by a KCNQ1 activator, ML277. It enhances the current amplitude, slows down activation, deactivation and inactivation kinetics, shifts the voltage dependence of activation to more positive voltages, decreases the Rb+/K+ permeability ratio, and selectively increases currents of mutant KCNQ1 channels that open only to the AO state. All these observations are consistent with the mechanism that ML277 specifically potentiates the AO state. On the other hand, ML277 does not affect the VSD activation, suggesting that it potentiates the AO state by enhancing the electromechanical (E-M) coupling when the VSD moves to the activated state. Our results suggest that ML277 provides a unique tool to investigate the gating mechanism of KCNQ1 and IKs channels. The specificity of ML277 to increase the AO state of native IKs currents also suggests a new strategy for anti-LQTS therapy.
Transcriptional Regulation and Mechanism of SigN (ZpdN), a pBS32 encoded Sigma Factor
Authors: Burton Aisha T. , DeLoughery Aaron , Li Gene-Wei , Kearns Daniel B. 
Published: May 2019

ABSTRACTLaboratory strains ofBacillus subtilisencodes as many as 16 alternative sigma factors, each dedicated to expressing a unique regulon such as those involved in stress resistance, sporulation, and motility. The ancestral strain ofB. subtilisalso encodes an additional sigma factor homolog, ZpdN, not found in lab strains due to it being encoded on the large, low copy number plasmid pBS32 that was lost during domestication. DNA damage triggers pBS32 hyper-replication and cell death in a manner that depends on ZpdN but how ZpdN mediates these effects was unknown. Here we show that ZpdN is a bona fide sigma factor that can direct RNA polymerase to transcribe ZpdN-dependent genes and we rename ZpdN to SigN accordingly. Rend-seq analysis was used to determine the SigN regulon on pBS32, and the 5’ ends of transcripts were used to predict the SigN consensus sequence. Finally, we characterize the regulation of SigN itself, and show that it is transcribed by at least three promoters:PsigN1, a strong SigA-dependent LexA-repressed promoter,PsigN2, a weak SigA-dependent constitutive promoter, andPsigN3, a SigN-dependent promoter. Thus, in response to DNA damage LexA is derepressed, SigN is expressed and then experiences positive feedback. How cells die in a pBS32-dependent manner remains unknown, but we predict that death is the product of expressing one or more genes in the SigN regulon.IMPORTANCESigma factors are utilized by bacteria to control and regulate gene expression. Extra cytoplasmic function sigma factors are activated during times of stress to ensure the survival of the bacterium. Here, we report the presence of a sigma factor that is encoded on a plasmid that leads to cellular death after DNA damage.
The effect of pupil size and peripheral brightness on detection and discrimination performance
Authors: Mathôt Sebastiaan , Ivanov Yavor 
Published: May 2019

AbstractIt is easier to read dark text on a bright background (positive polarity) than to read bright text on a dark background (negative polarity). This positive-polarity advantage is often linked to pupil size: A bright background induces small pupils, which in turn increases visual acuity. Here we report that pupil size, when manipulated through peripheral brightness, has qualitatively different effects on discrimination of fine stimuli in central vision and detection of faint stimuli in peripheral vision. Small pupils lead to improved discrimination performance, consistent with the positive-polarity advantage, but only for very small stimuli that are at the threshold of visual acuity. In contrast, large pupils lead to improved detection performance. These results are likely due to two pupil-size related factors: Small pupils increase visual acuity, which improves discrimination of fine stimuli; and large pupils increase light influx, which improves detection of faint stimuli. Light scatter is likely also a contributing factor: When a display is bright, light scatter creates a diffuse veil of retinal illumination that reduces image contrast, thus impairing detection performance. We further found that pupil size was larger during the detection task than during the discrimination task, even though both tasks were equally difficult and similar in visual input; this suggests that the pupil may automatically assume an optimal size for the current task. Our results may explain why pupils dilate in response to arousal: This may reflect an increased emphasis on detection of unpredictable danger, which is crucially important in many situations that are characterized by high levels of arousal. Finally, we discuss the implications of our results for the ergonomics of display design.
Single-molecule observation of ligand binding and conformational changes in FeuA
Authors: de Boer Marijn , Gouridis Giorgos , Abdillah Muthahari Yusran , Cordes Thorben 
Published: May 2019

ABSTRACTThe specific binding of ligands by proteins and the coupling of this process to conformational changes are fundamental to protein function. We designed a fluorescence-based single-molecule assay and data analysis procedure that allows the simultaneous real-time observation of ligand binding and conformational changes in FeuA. The substrate-binding protein FeuA binds the ligand ferri-bacillibactin and delivers it to the ABC importer FeuBC, which is involved in iron uptake in bacteria. The conformational dynamics of FeuA was assessed via Förster resonance energy transfer (FRET), whereas the presence of the ligand was probed by fluorophore quenching. We reveal that ligand binding shifts the conformational equilibrium of FeuA from an open to a closed conformation. Ligand binding occurs via an induced-fit mechanism, i.e., the ligand binds to the open state and subsequently triggers a rapid closing of the protein. However, FeuA also rarely samples the closed conformation without the involvement of the ligand. This shows that ligand interactions are not required for conformational changes in FeuA. However, ligand interactions accelerate the conformational change 10000-fold and temporally stabilize the formed conformation 250-fold.SIGNIFICANCE STATEMENTLigand binding and the coupling of this process to conformational changes in proteins are fundamental to their function. We developed a single-molecule approach that allows the simultaneous observation of ligand binding and conformational changes in the substrate-binding protein FeuA. This allows to directly observe the ligand binding process, ligand-driven conformational changes as well as rare short-lived conformational transitions that are uncoupled from the ligand. These findings provide insight into the fundamental relation between ligand-protein interactions and conformational changes. Our findings are, however, not only of interest to understand protein function, but the developed data analysis procedure allows the determination of (relative) distance changes in single-molecule FRET experiments, for situations in which donor and acceptor fluorophore are influenced by quenching processes.