bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cycloserine for Treatment of Multidrug-Resistant Tuberculosis in China: A Retrospective Observational Study
Authors: Li Yang , Wang Fei , Wu Limin , Zhu Min , He Guiqing , Sun Feng , Liu Qihui , Wang Xiaomeng , Zhang Wenhong 
Published: April 2018

AbstractObjectivesCycloserine is crucial in multidrug-resistant tuberculosis (MDR-TB) treatment. Although extensive research has been carried out on MDR-TB, most researchers have not treated cycloserine in much detail. Therefore, we evaluate the efficacy and safety of cycloserine and seek to clarify the role of cycloserine for treatment of simple MDR-TB, pre-extensively drug-resistant tuberculosis (pre-XDR-TB), and extensively drug-resistant tuberculosis (XDR-TB).Patients and methodsA retrospective observational study was performed in China. We determined the treatment outcome as the primary outcome for 144 cycloserine-treated and 181 cycloserine-nontreated patients according to the definitions of WHO. The proportion of patients with sputum-culture conversion and the frequency of adverse drug reactions related to cycloserine were assessed as well.ResultsAmong 325 MDR-TB patients, 144 were treated with cycloserine and 100 (69.4%) out of 144 successfully completed treatment. Compared with patients in non-cycloserine group, the hazard ratio of any unfavorable treatment outcome was 0.53 (95%CI: 0.35-0.81, P=0.003). Culture conversion rate at the intensive phase was similar whether cycloserine was administered or not (P=0.703). Of the 144 patients treated with cycloserine, a total of 16 (11.1%) patients experienced side-effects related to cycloserine, including 7 patients who discontinued cycloserine permanently.ConclusionsCycloserine could be an attractive agent to treat MDR-TB. Its safety profile warrants use in the most of MDR-TB cases. Cycloserine significantly improved the chance of favorable outcome for patients with simple MDR-TB but not pre-XDR-TB and XDR-TB. More aggressive regimens might be required for pre-XDR-TB or XDR-TB patients.
ERM proteins: The missing actin linkers in clathrin-mediated endocytosis
Authors: Kvalvaag Audun Sverre , Schink Kay Oliver , Brech Andreas , Sandvig Kirsten , Pust Sascha 
Published: April 2018

AbstractCanonical clathrin-coated pits (CCPs) are nucleated by the coordinated arrival of clathrin triskelia and AP2 adaptor proteins at phosphatidylinositol 4,5-bisphosphate (PIP2) enriched plasma membrane domains (1, 2). Subsequent propagation of the clathrin lattice helps to deform the membrane into a sharply curved pit (3). A large proportion of the initiated pits fall apart as abortive endocytic events within about 20 s, possibly due to insufficient cargo capture (4). Successful clathrin-mediated endocytosis (CME) is concluded when a clathrin-coated vesicle is released into the cell by dynamin-mediated fission of the CCP membrane neck (5, 6). A vast array of accessory proteins important for successful CME has been identified. Among these is actin, which has been shown to be required for the maturation and internalization of a subset of CCPs in human cells (7, 8). Actin dependency during CME correlates with elevated membrane tension, and CCP maturation requires actin polymerization during mitosis, in microvilli at the apical surface of polarized cells and in cells upon global mechanical stretching or hypotonic treatment (9–11). The Arp2/3 complex is thought to trigger an acute actin burst coinciding with CCP internalization, but how actin is recruited to CCPs in the first place is not known (12, 13). Here we show that the ERM (ezrin, radixin, moesin) protein family of membrane-actin linkers associates with CCPs, and that functional perturbation of ERM proteins impedes CCP maturation and reduces the rate of transferrin uptake. By total internal reflection fluorescence (TIRF) microscopy and unbiased object detection and tracking, we show that ezrin localizes to nascent CCPs and that these pits subsequently recruit actin. Based on these data, we propose a model in which activated ERM proteins recruit the initial actin filament during CME.
Pseudomonas aeruginosaCan Inhibit Growth of Streptococcal Species via Siderophore Production
Authors: Scott Jessie E. , Li Kewei , Filkins Laura M. , Zhu Bin , Kuchma Sherry L. , Schwartzman Joseph D. , O’Toole George A. 
Published: April 2018

AbstractCystic Fibrosis (CF) is a genetic disease that causes patients to accumulate thick, dehydrated mucus in the lung and develop chronic, polymicrobial infections due to reduced mucociliary clearance. These chronic polymicrobial infections and subsequent decline in lung function are significant factors in the morbidity and mortality of CF.Pseudomonas aeruginosaandStreptococcusspp. are among the most prevalent organisms in the CF lung; the presence ofP. aeruginosacorrelates with lung function decline and theStreptococcus millerigroup (SMG), a subgroup of the viridans streptococci, is associated with exacerbations in patients with CF. Here we characterize the interspecies interactions that occur between these two genera. We demonstrated that multipleP. aeruginosalaboratory strains and clinical CF isolates promote the growth of multiple SMG strains and oral streptococci in anin vitrococulture system. We investigated the mechanism by whichP. aeruginosaenhances growth of streptococci by screening for mutants ofP. aeruginosaPA14 unable to enhanceStreptococcusgrowth, and we identified theP. aeruginosa pqsL::TnMmutant, which failed to promote growth ofS. constellatusandS. sanguinis. Characterization of theP. aeruginosaΔpqsLmutant revealed that this strain cannot promoteStreptococcusgrowth. Our genetic data and growth studies support a model whereby theP. aeruginosaΔpqsLmutant overproduces siderophores, and thus likely outcompetesStreptococcus sanguinisfor limited iron. We propose a model whereby competition for iron represents one important means of interaction betweenP. aeruginosaandStreptococcusspp.ImportanceCystic fibrosis (CF) lung infections are increasingly recognized for their polymicrobial nature. These polymicrobial infections may alter the biology of the organisms involved in CF-related infections, leading to changes in growth, virulence and/or antibiotic tolerance, and could thereby affect patient health and response to treatment. In this study, we demonstrate interactions betweenP. aeruginosaand streptococci using a coculture model, and show that one interaction between these microbes is likely competition for iron. Thus, these data indicate that one CF pathogen may influence the growth of another and add to our limited knowledge of polymicrobial interactions in the CF airway.
Genome-wide analysis of cell cycle-regulating genes in the symbiotic dinoflagellate Symbiodinium minutum
Authors: Cato Michael L. , Jester Hallie D. , Lavertu Adam , Lyman Audrey , Tallent Lacey M. , Mitchell Geoffrey C. 
Published: April 2018

ABSTRACTA critical relationship exists between reef-building corals and their photosynthetic endosymbionts. As important as this relationship is for reef health, it is exquisitely delicate—exposure to temperatures only marginally above the average summer maximum can cause corals to bleach, expelling their resident algae. Interestingly, several studies indicate that failure of corals to properly regulate symbiont cell divisions at high temperatures may cause bleaching. This needs to be further investigated, but first, it is necessary to decipher the molecular mechanisms controlingl the cell division cycle in these organisms. As a first step toward this goal, we identified key cell cycle-regulating genes in the recently published genome of the symbiotic dinoflagellate Symbiodinium minutum. We then correlated expression of these genes with cell cycle phase in diurnally growing S. minutum in culture. Of particular interest, this approach allowed us to identify cyclins and cyclin-dependent kinases that are involved in the G1/S transition—a likely point for coral cells to exert control over algal cell divisions.
Microstructural Integrity of White Matter Moderates an Association Between Childhood Adversity and Adult Trait Anger
Authors: Kim M. Justin , Elliott Maxwell L. , d’Arbeloff Tracy C. , Knodt Annchen R. , Radtke Spenser R. , Brigidi Bartholomew D. , Hariri Ahmad R. 
Published: April 2018

AbstractAmongst a number of negative life sequelae associated with childhood adversity is the later expression of a higher dispositional tendency to experience anger and frustration to a wide range of situations (i.e., trait anger). We recently reported that an association between childhood adversity and trait anger is moderated by individual differences in both threat-related amygdala activity and executive control-related dorsolateral prefrontal cortex (dlPFC) activity, wherein individuals with relatively low amygdalaandhigh dlPFC activity do not express higher trait anger even when having experienced childhood adversity. Here, we examine possible structural correlates of this functional dynamic using diffusion magnetic resonance imaging data from 647 young adult men and women volunteers. Specifically, we tested whether the degree of white matter microstructural integrity as indexed by fractional anisotropy modulated the association between childhood adversity and trait anger. Our analyses revealed that higher microstructural integrity of multiple pathways was associated with an attenuated link between childhood adversity and adult trait anger. Amongst these pathways was the uncinate fasciculus, which not only provides a major anatomical link between the amygdala and prefrontal cortex but also is associated with individual differences in regulating negative emotion through top-down cognitive reappraisal. These findings suggest that higher microstructural integrity of distributed white matter pathways including but not limited to the uncinate fasciculus may represent an anatomical foundation serving to buffer against the expression of childhood adversity as later trait anger, which is itself associated with multiple negative health outcomes.
Functional Balance between TCF21-Slug defines phenotypic plasticity and sub-classes in high-grade serous ovarian cancer
Authors: Varankar Sagar S , Kamble Swapnil C , Mali Avinash M , More Madhuri M , Abraham Ancy , Kumar Brijesh , Pansare Kshama J. , Narayanan Nivedhitha J , Sen Arijit , Dhake Rahul D , Joshi Aparna N , Midha Divya , Jolly Mohit Kumar , Dong Ying , Clements Judith A , Bapat Sharmila A 
Published: April 2018

AbstractCellular plasticity and transitional phenotypes add to complexities of cancer metastasis initiated by single cell epithelial to mesenchymal transition or cooperative cell migration (CCM). We identified novel regulatory cross-talks between Tcf21 and Slug in mediating phenotypic and migration plasticity in high-grade serous ovarian adenocarcinoma. Live imaging discerned CCM as being achieved either through rapid cell proliferation or sheet migration. Transitional states were enriched over the rigid epithelial or mesenchymal phenotypes under conditions of environmental stresses. The Tcf21-Slug interplay identified in HGSC tumors through effective stratification of subtypes also contributed to class-switching in response to disease progression or therapy. Our study effectively provides a framework for understanding the relevance of cellular plasticity in situ as a function of two transcription factors.
The Integrative Conjugative Element (ICE) ofMycoplasma agalactiae: key elements involved in horizontal dissemination and influence of co-resident ICEs
Authors: Baranowski Eric , Dordet-Frisoni Emilie , Sagné Eveline , Hygonenq Marie-Claude , Pretre Gabriela , Claverol Stéphane , Fernandez Laura , Nouvel Laurent Xavier , Citti Christine 
Published: April 2018

ABSTRACTThe discovery of integrative conjugative elements (ICEs) in wall-less mycoplasmas and the demonstration of their role in massive gene flows within and across species has shed new light on the evolution of these minimal bacteria. Of these, ICEA of the ruminant pathogenMycoplasma agalactiaerepresents a prototype and belongs to a new clade of the Mutatorlike superfamily that has no preferential insertion site and often occurs as multiple chromosomal copies. Here, functional genomics and mating experiments were combined to address ICEA functions and define the minimal ICEA chassis conferring conjugative properties toM. agalactiae. Data further indicated a complex interaction among co-resident ICEAs, since the minimal ICEA structure was influenced by the occurrence of additional ICEA copies that cantrans-complement conjugative-deficient ICEAs. However, this cooperative behavior was limited to the CDS14 surface lipoprotein, which is constitutively expressed by co-resident ICEAs, and did not extend to other ICEA proteins including thecis-acting DDE recombinase and components of the mating channel whose expression was only sporadically detected. Remarkably, conjugative-deficient mutants containing a single ICEA copy knocked-out incdsl4can be complemented by neighboring cells expressing CDS14. This result, together with the conservation of CDS14 functions in closely related species, may suggest a way for mycoplasma ICEs to extend their interaction outside of their chromosomal environment. Overall, this study provides a first model of conjugative transfer in mycoplasmas and offers valuable insights towards the understanding of horizontal gene transfer in this highly adaptive and diverse group of minimal bacteria.IMPRTANCEIntegrative conjugative elements (ICEs) are self-transmissible mobile genetic elements that are key mediators of horizontal gene flow in bacteria. Recently, a new category of ICEs has been identified that confer conjugative properties to mycoplasmas, a highly adaptive and diverse group of wall-less bacteria with reduced genomes. Unlike classical ICEs, these mobile elements have no preferential insertion specificity and multiple mycoplasma ICE copies can be found randomly integrated into the host chromosome. Here, the prototype ICE ofMycoplasma agalactiaewas used to define the minimal conjugative machinery and propose the first model of ICE transfer in mycoplasmas. This model unveils the complex interactions taking place among co-resident ICEs and suggests a way for these elements to extend their influence outside of their chromosomal environment. These data pave the way for future studies aiming at deciphering chromosomal transfer, an unconventional mechanism of DNA swapping that has been recently associated with mycoplasma ICEs.
Meta-analysis of RNA-seq studies reveals genes responsible for life stage-dominant functions in Schistosoma mansoni
Authors: Lu Zhigang , Berriman Matthew 
Published: April 2018

AbstractBackgroundSince the genome of the parasitic flatworm Schistosoma mansoni was sequenced in 2009, various RNA-seq studies have been conducted to investigate differential gene expression between certain life stages. Based on these studies, the overview of gene expression in all life stages can improve our understanding of S. mansoni genome biology.Methodspublicly available RNA-seq data covering all life stages and gonads were mapped to the latest S. mansoni genome. Read counts were normalised across all samples and differential expression analysis was preformed using the generalized linear model (GLM) approach.Resultswe revealed for the first time the dissimilarities among all life stages. Genes that are abundantly-expressed in all life stages, as well as those preferentially-expressed in certain stage(s), were determined. The latter reveals genes responsible for stage-dominant functions of the parasite, which can be a guidance for the investigation and annotation of gene functions. In addition, distinct differential expression patterns were observed between adjacent life stages, which not only correlate well with original individual studies, but also provide additional information on changes in gene expression during parasite transitions. Furthermore, thirteen novel housekeeping genes across all life stages were identified, which is valuable for quantitative studies (e.g., qPCR).Conclusionsthe metaanalysis provides valuable information on the expression and potential functions of S. mansoni genes across all life stages, and can facilitate basic as well as applied research for the community.
Quantification of biases in predictions of protein stability changes upon mutations
Authors: Pucci F. , Bernaerts K. , Kwasigroch J. M. , Rooman M. 
Published: April 2018

AbstractBioinformatics tools that predict protein stability changes upon point mutations have made a lot of progress in the last decades and have become accurate and fast enough to make computational mutagenesis experiments feasible, even on a proteome scale. Despite these achievements, they still suffer from important issues that must be solved to allow further improving their performances and utilizing them to deepen our insights into protein folding and stability mechanisms. One of these problems is their bias towards the learning datasets which, being dominated by destabilizing mutations, causes predictions to be better for destabilizing than for stabilizing mutations.We thoroughly analyzed the biases in the prediction of folding free energy changes upon point mutations (ΔΔG0) and proposed some unbiased solutions. We started by constructing a dataset Ssymof experimentally measured ΔΔG0s with an equal number of stabilizing and destabilizing mutations, by collecting mutations for which the structure of both the wild type and mutant protein is available. On this balanced dataset, we assessed the performances of fifteen widely usedΔΔG0predictors. After the astonishing observation that almost all these methods are strongly biased towards destabilizing mutations, especially those that use black-box machine learning, we proposed an elegant way to solve the bias issue by imposing physical symmetries under inverse mutations on the model structure, which we implemented in PoPMuSiCsym. This new predictor constitutes an efficient trade-off between accuracy and absence of biases. Some final considerations and suggestions for further improvement of the predictors are discussed.
Discovery of Large Disjoint Motif in Biological Network using Dynamic Expansion Tree
Authors: Patra Sabyasachi , Mohapatra Anjali 
Published: April 2018

AbstractNetwork motifs play an important role in structural analysis of biological networks. Identification of such network motifs leads to many important applications, such as: understanding the modularity and the large-scale structure of biological networks, classification of networks into super-families etc. However, identification of network motifs is challenging as it involved graph isomorphism which is computationally hard problem. Though this problem has been studied extensively in the literature using different computational approaches, we are far from encouraging results. Motivated by the challenges involved in this field we have proposed an efficient and scalable Motif discovery algorithm using a Dynamic Expansion Tree (MDET). In this algorithm embeddings corresponding to child node of expansion tree are obtained from the embeddings of parent node, either by adding a vertex with time complexity O(n) or by adding an edge with time complexity O(1) without involving any isomorphic check. The growth of Dynamic Expansion Tree (DET) depends on availability of patterns in the target network. DET reduces space complexity significantly and the memory limitation of static expansion tree can overcome. The proposed algorithm has been tested on Protein Protein Interaction (PPI) network obtained from MINT database. It is able to identify large motifs faster than most of the existing motif discovery algorithms.
ADAR2 mediated Q/R editing of GluK2 regulates homeostatic plasticity of kainate receptors
Authors: Gurung Sonam , Evans Ashley J. , Wilkinson Kevin A. , Henley Jeremy M. 
Published: April 2018

AbstractKainate receptors (KARs) are heteromeric glutamate-gated ion channels that regulate neuronal excitability and network function in the brain. Most KARs contain the subunit GluK2 and the precise properties of these GluK2-containing KARs are determined by additional factors including ADAR2-mediated mRNA editing of a single codon that changes a genomically encoded glutamine (Q) to arginine (R) in the pore-lining region of GluK2. ADAR2-dependent Q/R editing of GluK2 is dynamically regulated during homeostatic plasticity (scaling) elicited by suppression of synaptic activity with TTX. Here we show that TTX decreases levels of ADAR2 by enhancing its proteasomal degradation. This selectively reduces the numbers of GluK2 subunits that are edited and increases the surface expression of GluK2-containing KARs. Furthermore, we show that partial ADAR2 knockdown phenocopies and occludes TTX-induced scaling of KARs. These data indicate that activity-dependent regulation of ADAR2 proteostasis and GluK2 Q/R editing provides a mechanism for KAR homeostatic plasticity.
Synchrotron radiation external beam rotational radiotherapy of breast cancer: proof of principle
Authors: Di Lillo Francesca , Mettivier Giovanni , Castriconi Roberta , Sarno Antonio , Stevenson Andrew W. , Hall Chris J. , Häusermann Daniel , Russo Paolo 
Published: April 2018

The principle of rotational summation of the absorbed dose for breast cancer treatment with orthovoltage X-ray beams was proposed by J. Boone in 2012. Here, use of X-ray synchrotron radiation for image guided external beam rotational radiotherapy treatment of breast cancer is proposed. Tumor irradiation occurs with the patient in the prone position hosted on a rotating bed, with her breast hanging from a hole in the bed, which rotates around a vertical axis passing through the tumor site. Horizontal collimation of the X-ray beam provides for whole breast or partial breast irradiation, while vertical translation of the bed and successive rotations allow for irradiation of the full tumor volume, with dose rates which permit also hypofractionated treatments. In this work, which follows a previous preliminary report, results are shown of a full series of measurements on polyethylene and acrylic cylindrical phantoms carried out at the Australian Synchrotron, confirmed byGeant4Monte Carlo simulations, intended to demonstrate the proof of principle of the technique. Dose measurements were carried out with calibrated ion chambers, radiochromic films and thermoluminescence dosimeters. The photon energy investigated was 60 keV. Image guidance may occur with the transmitted beam for contrast-enhanced breast computed tomography. For a horizontal beam collimation of 1.5 cm and rotation around the central axis of a 14 cm-diameter polyethylene phantom, a periphery-to-center dose ratio of 14% was measured. The simulations showed that under the same conditions the dose ratio decreases with increasing photon energy down to 10% at 175 keV. These values are comparable with those achievable with conventional megavoltage radiotherapy of breast cancer with a medical linear accelerator. Dose painting was demonstrated with two off-center `cancer foci' with 1.3 Gy and 0.6 Gy target doses. The use of a radiosensitizing agent for dose enhancement is foreseen.