bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mucosal Monosaccharide Transporter Expression in Newborns With Jejunoileal Atresia and Along the Adult Intestine
Authors: Meier Chantal Florence , Camargo Simone Mafalda Rodrigues , Hunziker Schirin , Leu Svenja , Holland‐Cunz Stefan Gerhard , Verrey François , Vuille‐dit‐Bille Raphael Nicolas 
Published: June 2019

ABSTRACTObjectives:In newborn rodents, intestinal maturation involves delayed fructose transporter GLUT5 expression until weaning. In jejunoileal atresia (JIA), distal intestinal segments lack exposure to amniotic fluid‐containing carbohydrates. We assessed in human newborns, the impact of intestinal maturation and obstruction on mucosal monosaccharide transporter expression.Methods:Samples were obtained from 10 newborns operated for small intestinal atresia and from 17 adults undergoing gastroduodenoscopy and/or ileocolonoscopy. mRNA expression of the transporters SGLT1, GLUT1, GLUT2, GLUT5, and GLUT7 was measured in neonate samples proximal and distal of the atresia as well as in adult duodenum, ileum, and colon. Protein expression and localization was assessed using immunofluorescence.Results:Although mRNA expression of monosaccharide transporters did not significantly differ between newborn and adult samples, luminal fructose transporter GLUT5 protein was absent in 0‐ to 4‐day‐old neonates, but expressed in adults. The mRNA expression of the 5 tested monosaccharide transporters was unchanged distal from the JIA relative to proximal. Similarly, luminal sodium‐dependent glucose transporter SGLT1 and basolateral GLUT2 were expressed proximal and distal to JIA as visualized by immunofluorescence staining. With the exception of glucose transporter GLUT1 that showed highest expression levels in colon, all investigated hexose transporters showed strongest expression in duodenum, lower levels in ileum and lowest in colon.Conclusions:Human newborns lack small intestinal fructose transporter GLUT5 protein expression and small intestinal atresia does not affect the expression of hexose transporters.
Prediction of Thiopurine Metabolite Levels Based on Haematological and Biochemical Parameters
Authors: Hradsky Ondrej , Potuznikova Kristyna , Siroka Jitka , Lerchova Tereza , Urbanek Lubor , Mihal Vladimir , Spenerova Michaela , Velganova‐Veghova Maria , Karaskova Eva , Bronsky Jiri 
Published: June 2019

ABSTRACTObjectives:Therapeutic drug monitoring of thiopurine erythrocyte levels is not available in all centers and it usually requires quite a long time to obtain the results. The aims of this study were to build a model predicting low levels of 6‐thioguanine and 6‐methylmercaptopurine in pediatric inflammatory bowel disease (IBD) patients and to build a model to predict nonadherence in patients treated with azathioprine (AZA).Methods:The study consisted of 332 observations in 88 pediatric IBD patients. Low AZA dosing was defined as 6‐thioguanine levels <125 pmol/8 × 108 erythrocytes and 6‐methylmercaptopurine levels <5700 pmol/8 × 108 erythrocytes. Nonadherence was defined as undetectable levels of 6‐thioguanine and 6‐methylmercaptopurine <240 pmol/8 × 108 erythrocytes. Data were divided into training and testing part. To construct the model predicting low 6‐thioguanine levels, nonadherence, and the level of 6‐thioguanine, the modification of random forest method with cross‐validation and resampling was used.Results:The final models predicting low 6‐thioguanine levels and nonadherence had area under the curve, 0.87 and 0.94; sensitivity, 0.81 and 0.82; specificity, 0.80 and 86; and distance, 0.31 and 0.21, respectively, when applied on the testing part of the dataset. When the final model for prediction of 6‐thioguanine values was applied on testing dataset, a root‐mean‐square error of 110 was obtained.Conclusions:Using easily obtained laboratory parameters, we constructed a model with sufficient accuracy to predict patients with low 6‐thioguanine levels and a model for prediction of AZA treatment nonadherence (web applications: https://hradskyo.shinyapps.io/6TG_prediction/ and https://hradskyo.shinyapps.io/Non_adherence/).
Spatial-Temporal Epidemiology of the Syphilis Epidemic in Relation to Neighborhood-Level Structural Factors in British Columbia, 2005–2016
Authors: Salway Travis , Gesink Dionne , Lukac Christine , Roth David , Ryan Venessa , Mak Sunny , Wang Susan , Newhouse Emily , Hayden Althea , Bharmal Aamir , Hoyano Dee , Morshed Muhammad , Grennan Troy , Gilbert Mark , Wong Jason 
Published: June 2019

Background
Spatial clusters of syphilis have been observed within several jurisdictions globally; however, the degree to which they are predicted by the spatial distributions of gay, bisexual, and other men who have sex with men (GBM) and testing remains unknown. We sought to describe the spatial-temporal epidemiology of infectious syphilis and identify associations between neighborhood-level factors and rates of syphilis, in British Columbia, Canada.

Methods
We used ArcGIS to map infectious syphilis cases among men (2005 to 2016), SaTScan to detect areas with significantly elevated rates of syphilis, and spatial regression to identify associations between neighborhood-level factors and rates of syphilis.

Results
Five clusters were identified: a core in downtown Vancouver (incidence rate ratio [IRR], 18.0; 2007–2016), 2 clusters adjacent to the core (IRR, 3.3; 2012–2016; and IRR, 2.2; 2013–2016), 1 cluster east of Vancouver (IRR, 2.1; 2013–2016), and 1 cluster in Victoria (IRR, 4.3; 2015–2016). Epidemic curves were synchronized across cluster and noncluster regions. Neighborhood-level GBM population estimates and testing rates were both associated with syphilis rates; however, the spatial distribution of syphilis was not fully explained by either of these factors.

Conclusions
We identified two novel ecologic correlates of the spatial distribution of infectious syphilis—density of GBM and rates of syphilis testing—and found that these factors partially, though not entirely, explained the spatial distribution of clusters. Residual spatial autocorrelation suggests that greater syphilis testing coverage may be needed and low-barrier GBM-affirming testing should be expanded to regions outside the core.
Detectability of Malignant Lesions by Whole-Body Magnetic Resonance Imaging Using Whole-Body Integrated Positron Emission Tomography/Magnetic Resonance Imaging
Authors: Ishii Shiro , Miyajima Masayuki , Suenaga Hiroki , Sugawara Shigeyasu , Nemoto Ayaka , Ukon Naoyuki , Nambu Takeyuki , Kubo Hitoshi , Oriuchi Noboru , Ito Hiroshi 
Published: June 2019

Purpose
To assess the diagnostic ability of whole-body magnetic resonance imaging (MRI) using integrated positron emission tomography/MRI(PET/MRI).

Methods
Axial T2-weighted image (T2WI), diffusion-weighted imaging (DWI), coronal T1-weighted image (T1WI), axial volumetric interpolated breath-hold examination in the lung field, and 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG–PET) were evaluated in combination with T2WI alone, T2WI + DWI, T2WI + DWI + T1WI, T2WI + DWI + T1WI + volumetric interpolated breath-hold examination (all MRI images), and all MRI + FDG-PET.

Results
A total of 370 lesions were observed in 90 (62.5%) of the 144 patients. The lesion-based sensitivities were 62%, 74%, 74%, 76%, and 94%, and the patient-based sensitivities were 70%, 77%, 77%, 77%, and 81% using T2WI, T2WI + DWI, T2WI + DWI + T1WI, all MRI, and all MRI + FDG-PET, respectively. There were significant differences in the lesion-based sensitivity between T2WI and other sequence combinations and between all MRI and all MRI + FDG-PET. No significant differences were observed between any combinations among the patient-based sensitivities.

Conclusion
The sensitivity of whole-body MRI was lower when lesion based, but almost equivalent when patient based compared with PET/MRI.
Properties of a Multidimensional Landscape Model for Determining Cellular Network Thermodynamics
Authors: Hubbard Joseph B. , Halter Michael , Plant Anne L. 
Published: June 2019

ABSTRACTThe steady state distributions of phenotypic responses within an isogenic population of cells result from both deterministic and stochastic characteristics of biochemical networks. A biochemical network can be characterized by a multidimensional potential landscape based on the distribution of responses and a diffusion matrix of the correlated dynamic fluctuations between N-numbers of intracellular network variables. The Boltzmann H-function defines the rate of free energy dissipation of a network system and provides a framework for determining the heat associated with the nonequilibrium steady state and its network components. We conjecture that there is an upper limit to the rate of dissipative heat produced by a biological system, and we show that the dissipative heat has a lower bound. The magnitudes of the landscape gradients and the dynamic correlated fluctuations of network variables are experimentally accessible, and through an analysis that we refer to as Thermo-Fokker-Planck (Thermo-FP), provide insight into the composition of the network and the relative thermodynamic contributions from network components. We surmise that these thermodynamic quantities allow determination of the relative importance of network components to overall network control.
Genome maintenance functions ofTrypanosoma bruceiDNA Polymerase N include telomere association and a role in antigenic variation
Authors: Leal Andrea Zurita , Schwebs Marie , Briggs Emma , Reis Helena , Lemgruber Leandro , Luko Katarina , Butter Falk , McCulloch Richard , Janzen Christian J. 
Published: June 2019

AbstractMaintenance of genome integrity is critical to guarantee transfer of an intact genome from parent to offspring during cell division. DNA polymerases (Pols) provide roles in both replication of the genome and the repair of a wide range of lesions. Amongst replicative DNA Pols, translesion DNA Pols play a particular role: replication to bypass DNA damage, often at the cost of mutation. All cells express a range of translesion Pols, but little work has examined their function in parasites, including whether the enzymes might contribute to host-parasite interactions. Here, we describe a dual function of translesion PolN in African trypanosomes. Previously we demonstrated that PolN is associated with telomeric sequences and now we show that RNAi-mediated depletion of PolN results in slowed growth, altered DNA content, changes in cell morphology, and increased sensitivity to DNA damaging agents. Depletion of PolN leads to chromosome segregation defects and accumulation of DNA damage. We also show that PolN displays discrete localisation at the nuclear periphery in the absence of exogenous DNA damage. In addition, we demonstrate that PolN depletion leads to deregulation of telomeric variant surface glycoprotein genes, linking the function of this translesion DNA polymerase to host immune evasion by antigenic variation.
Computational analysis of transcriptome signature repurposes low dose trifluoperazine for the treatment of fragile X syndrome in mouse model
Authors: Ding Qi , Sethna Ferzin , Wu Xue-Ting , Miao Zhuang , Chen Ping , Zhang Yueqi , Xiao Hua , Feng Wei , Feng Yue , Li Xuan , Wang Hongbing 
Published: June 2019

ABSTRACTFragile X syndrome (FXS), caused by mutations in fragile X mental retardation 1 gene (FMR1), is a prevailing genetic disorder of intellectual disability and autism. Currently, there is no efficacious medication for FXS. Here, we use transcriptome landscape as a holistic molecular phenotype/endpoint to identify potential therapeutic intervention. Through in silicoscreening with public gene signature database, computational analysis of transcriptome profile inFmr1knockout (KO) neurons predicts therapeutic value of an FDA-approved drug trifluoperazine. Through experimental validation, we find that systemic administration of low dose trifluoperazine at 0.05 mg/kg attenuates multiple FXS- and autism-related behavioral symptoms. Moreover, computational analysis of transcriptome alteration caused by trifluoperazine suggests a new mechanism of action against PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) activity. Consistently, trifluoperazine suppresses PI3K activity and its down-stream targets Akt (protein kinase B) and S6K1 (S6 kinase 1) in neurons. Further, trifluoperazine normalizes the aberrantly elevated activity of Akt and S6K1 and enhanced protein synthesis in FXS mouse. In conclusion, our data demonstrate promising value of gene signature-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders, and suggest trifluoperazine as a potential practical treatment for FXS.
Dancing Molecules: Rewiring Cooperative Communications within 14-3-3 ζ Docking Proteins
Authors: Davis Leroy K. 
Published: June 2019

AbstractAllosteric engineering may play a key role in novel drug discovery. As allosteric interactions are often associated with disease states where protein active sites are rendered constitutively active. Due to their role in regulating signal transduction in cells, we attempted to rewire cooperative communications within the 14-3-3 ζ docking protein. To avoid disruption of evolutionarily tuned interaction networks, we attempted to do so by applying the “Fundamental Theory of the Evolution Force: FTEF”. Whereby, we reversed the motion vector of the 14-3-3 ζ C’ terminal tail. We were also able to modify low frequency vibrational modes across 14-3-3 ζ conformational ensembles. Notably, synthetic evolution by FTEF anticipated evolution of the 14-3-3 ζ docking protein. And accentuated nonrandom patterns of deformation waves resulting in a gain of function mutation characterized by increased protein flexibility. As well as allowed us to discover a genome encoded spatial arrangement of strain that promotes translation of vibrational motions through protein structural layers. We also discovered a 14-3-3 ζ evolution blueprint that predetermines evolutional fate of the docking protein. The aforementioned suggests that the evolutionary fate of cells may be encoded in the genome, thusly may be predetermined.
SignificanceAllostery plays a key role in disease. Wherein, mutations redistribute conformational ensembles and render proteins constitutively active. 14-3-3 docking proteins are key signaling proteins involved in multiple signal pathways that effect cell proliferation, cell cycle and apoptosis. Saliently, the 14-3-3 ζ isoform is associated with neurodegenerative disease, cancer and glaucoma. Thusly, ability to rewire cooperative communications within 14-3-3 ζ offers opportunity for novel drug discovery.
Ammonia inhibits energy metabolism in astrocytes in a rapid and GDH2-dependent manner
Authors: Drews Leonie , Zimmermann Marcel , Poss Rebecca E. , Brilhaus Dominik , Bergmann Laura , Wiek Constanze , Piekorz Roland P. , Weber Andreas P.M. , Mettler-Altmann Tabea , Reichert Andreas S. 
Published: June 2019

AbstractIn hepatic encephalopathy (HE) astrocyte dysfunction is a primary factor impairing neuronal activity under hyperammonemia. We show that mitochondria in cellular HE models undergo rapid fragmentation under hyperammonemia in a reversible manner. Mitochondrial respiration and glycolysis were instantaneously hampered in a pH-independent manner. A metabolomics approach revealed a subsequent accumulation of numerous amino acids, including branched chain amino acids, and glucose. N15labeling of ammonia shows rapid incorporation of ammonia-derived nitrogen into glutamate and glutamate-derived amino acids. Downregulating humanGLUD2, encoding mitochondrial glutamate dehydrogenase 2 (GDH2), inhibiting GDH2 activity by SIRT4 overexpression, and supplementing cells with glutamate or glutamine alleviated ammonia-induced inhibition of mitochondrial respiration. Thus, under hyperammonemic conditions, GDH2 catalyzes the removal of ammonia by reductive amination of α-ketoglutarate but at the same time inhibits the TCA-cycle by depleting α-ketoglutarate. Overall, we propose a mitochondria-dependent mechanism contributing to the early steps in the pathogenesis of HE where the interplay between energy metabolism and ammonia removal plays a pivotal role.
Neuromedin U signaling regulates memory retrieval of learned salt avoidance in aC. elegansgustatory circuit
Authors: Watteyne Jan , Van der Auwera Petrus , Peymen Katleen , Borghgraef Charline , Vandewyer Elke , Rutten Iene , Lammertyn Jeroen , Jelier Rob , Schoofs Liliane , Beets Isabel 
Published: June 2019

AbstractLearning and memory are regulated by neuromodulatory pathways, but the contribution and temporal requirement of most neuromodulators in a learning circuit are unknown. Here we identify the evolutionarily conserved neuromedin U (NMU) neuropeptide family as a regulator of memory retrieval inC. elegansgustatory aversive learning. The NMU homolog CAPA-1 and its receptor NMUR-1 are required for the expression of learned salt avoidance. Aversive learning depends on the release of CAPA-1 neuropeptides from sensory ASG neurons that respond to salt stimuli in an experience-dependent manner. Optogenetic silencing of CAPA-1 neurons blocks the immediate retrieval, but not the acquisition, of learned salt avoidance. CAPA-1 subsequently signals through NMUR-1 in AFD sensory neurons to modulate two navigational strategies for salt chemotaxis. Aversive conditioning thus recruits NMU signaling to eventually modulate locomotor programs for expressing learned avoidance behavior. Because NMU signaling is conserved across bilaterian animals, our findings incite further research into its function in other memory and decision-making circuits.Graphical Abstract
GC-AG Introns Features in Long Non-coding and Protein-Coding Genes Suggest Their Role in Gene Expression Regulation
Authors: Alezz Monah Abou , Celli Ludovica , Belotti Giulia , Lisa Antonella , Bione Silvia 
Published: June 2019

ABSTRACTLong non-coding RNAs (lncRNAs) are recognized as an important class of regulatory molecules involved in a variety of biological functions. However, the regulatory mechanisms of long non-coding genes expression are still poorly understood. The characterization of the genomic features of lncRNAs is crucial to get insight into their function. In this study, we exploited recent annotations by GENCODE to characterize the genomic and splicing features of long non-coding genes in comparison with protein-coding ones, both in human and mouse. Our analysis highlighted differences between the two classes of genes in terms of their gene architecture. Significant differences in the splice sites usage were observed between long non-coding and protein-coding genes (PCG). While the frequency of non-canonical GC-AG splice junctions represents about 0.8% of total splice sites in PCGs, we identified a significant enrichment of the GC-AG splice sites in long non-coding genes, both in human (3.0%) and mouse (1.9%). In addition, we found a positional bias of GC-AG splice sites being enriched in the first intron in both classes of genes. Moreover, a significant shorter length and weaker donor and acceptor sites were found comparing GC-AG introns to GT-AG introns. Genes containing at least one GC-AG intron were found conserved in many species, more prone to alternative splicing and a functional analysis pointed toward their enrichment in specific biological processes such as DNA repair. Our study shows for the first time that GC-AG introns are mainly associated with lncRNAs and are preferentially located in the first intron. Additionally, we discovered their regulatory potential indicating the existence of a new mechanism of non-coding and PCGs expression regulation.
SilencingPHOSPHOENOLPYRUVATE CARBOXYLASE1in the Obligate Crassulacean Acid Metabolism SpeciesKalanchoë laxifloracauses Reversion to C3-like Metabolism and Amplifies Rhythmicity in a Subset of Core Circadian Clock Genes
Authors: Boxall Susanna F. , Kadu Nirja , Dever Louisa V. , Kneřová Jana , Waller Jade L. , Gould Peter J. D. , Hartwell James 
Published: June 2019

ABSTRACTUnlike C3plants, Crassulacean acid metabolism (CAM) plants fix CO2in the dark using phosphoenolpyruvate carboxylase (PPC; EC 4.1.1.31). PPC combines PEP with CO2(as HCO3−), forming oxaloacetate that is rapidly converted to malate, leading to vacuolar malic acid accumulation that peaks phased to dawn. In the light period, malate decarboxylation concentrates CO2around RuBisCO for secondary fixation. CAM mutants lacking PPC have not been described. Here, RNAi was employed to silence CAM isogenePPC1inKalanchoë laxiflora. LinerPPC1-BlackedPPC1transcripts, PPC activity, dark period CO2fixation, and nocturnal malate accumulation. Light period stomatal closure was also perturbed, and the plants displayed reduced but detectable dark period stomatal conductance, and arrhythmia of the CAM CO2fixation circadian rhythm under constant light and temperature (LL) free-running conditions. By contrast, the rhythm of delayed fluorescence was enhanced in plants lackingPPC1. Furthermore, a subset of gene transcripts within the central circadian oscillator were up-regulated and oscillated robustly. The regulation guard cell genes involved controlling stomatal movements was also altered inrPPC1-B. This provided direct evidence that altered regulatory patterns of key guard cell signaling genes are linked with the characteristic inverse pattern of stomatal opening and closing during CAM.
Scaffold subunits support associated subunit assembly in theChlamydomonasciliary nexin-dynein regulatory complex
Authors: Gui Long , Song Kangkang , Tristchler Douglas , Bower Raqual , Si Yan , Dai Aguang , Augsperger Katherine , Sakizadeh Jason , Grzemska Magdalena , Ni Thomas , Porter Mary E. , Nicastro Daniela 
Published: June 2019

ABSTRACTThe nexin-dynein regulatory complex (N-DRC) in motile cilia and flagella functions as a linker between neighboring doublet microtubules, acts to stabilize the axonemal core structure, and serves as a central hub for the regulation of ciliary motility. Although the N-DRC has been studied extensively using genetic, biochemical, and structural approaches, the precise arrangement of the eleven (or more) N-DRC subunits remains unknown. Here, using cryo-electron tomography, we have compared the structure ofChlamydomonaswild-type flagella to that of strains with specific DRC subunit deletions or rescued strains with tagged DRC subunits. Our results show that DRC7 is a central linker subunit that helps connect the N-DRC to the outer dynein arms. DRC11 is required for the assembly of DRC8, and DRC8/11 form a sub-complex in the proximal lobe of the linker domain that is required to form stable contacts to the neighboring B-tubule. Gold labeling of tagged subunits determines the precise locations of the previously ambiguous N-terminus of DRC4 which is now shown to contribute to the core scaffold of the N-DRC and C-terminus of DRC5. Our results reveal the overall architecture of N-DRC, with the three subunits, DRC1/2/4 forming a core complex that serves as the scaffold for the assembly of the “functional subunits” associate, namely DRC3/5-8/11. These findings shed light on N-DRC assembly and its role in regulating flagellar beating.Significance StatementCilia and flagella are small hair-like appendages in eukaryotic cells that play essential roles in cell sensing, signaling, and motility. The highly conserved nexin-dynein regulatory complex (N-DRC) is one of the key regulators for ciliary motility. At least 11 proteins (DRC1–11) have been assigned to the N-DRC, but their precise arrangement within the large N-DRC structure is not yet known. Here, using cryo-electron tomography combined with genetic approaches, we have localized DRC7, the sub-complex DRC8/DRC11, the N-terminus of DRC4, and the C-terminus of DRC5. Our results provide insights into the N-DRC structure, its function in the regulation of dynein activity, and the mechanism by whichn-drcmutations can lead to defects in ciliary motility that cause disease.