bluuebunny/crossref_metadata_2025_split huggingface dataset:
Time-resolved mapping of genetic interactions to model rewiring of signaling pathways
Authors: Heigwer Florian , Scheeder Christian , Miersch Thilo , Schmitt Barbara , Blass Claudia , Pour-Jamnani Mischan Vali , Boutros Michael 
Published: August 2018

AbstractContext-dependent changes in genetic vulnerabilities are important to understand the wiring of cellular pathways and variations in different environmental conditions. However, methodological frameworks to investigate the plasticity of genetic networks over time or in response to external stresses are lacking. To analyze the plasticity of genetic interactions, we performed an arrayed combinatorial RNAi screen inDrosophilacells at multiple time points and after pharmacological inhibition of Ras signaling activity. Using an image-based morphology assay to capture a broad range of phenotypes, we assessed the effect of 12768 pairwise RNAi perturbations in six different conditions. We found that genetic interactions form in different trajectories and developed an algorithm, termed MODIFI, to analyze how genetic interactions rewire over time. Using this framework, we identified more statistically significant interactions compared to endpoints assays and further observed several examples of context-dependent crosstalk between signaling pathways such as an interaction between Ras and Rel which is dependent on MEK activity.
De Novo Mutational Signature Discovery in Tumor Genomes using SparseSignatures
Authors: Lal Avantika , Liu Keli , Tibshirani Robert , Sidow Arend , Ramazzotti Daniele 
Published: August 2018

AbstractCancer is the result of mutagenic processes that can be inferred from tumor genomes by analyzing rate spectra of point mutations, or “mutational signatures”. Here we present SparseSignatures, a novel framework to extract signatures from somatic point mutation data. Our approach incorporates a user-specified background signature, employs regularization to reduce noise in non-background signatures, uses cross-validation to identify the number of signatures, and is scalable to large datasets. We show that SparseSignatures outperforms current state-of-the-art methods on simulated data using a variety of standard metrics. We then apply SparseSignatures to whole genome sequences of pancreatic and breast tumors, discovering well-differentiated signatures that are linked to known mutagenic mechanisms and are strongly associated with patient clinical features.Authors SummaryCancer is a genetic disease, occurring as a result of mutagenic processes causing DNA somatic mutations in genes controlling cellular growth and division. These somatic mutations arise from processes such as defective DNA repair and environmental mutagens, which massively increase the rate of somatic variants. As a result, due to the specificity of molecular lesions caused by such processes, and the specific repair mechanisms deployed by the cell to mitigate the damage, mutagenic processes generate characteristic point mutation rate spectra which are called mutational signatures. These signatures can indicate which mutagenic processes are active in a tumor, reveal biological differences between cancer subtypes, and may be useful markers for therapeutic response. Here, we develop SparseSignatures, a novel framework for mutational signature discovery capable of both identifying the active signatures in a dataset of point mutations and calculating their exposure values, i.e., the number of mutations originating from each signature in each patient. We show that our approach outperforms current state-of-the-art methods on simulated data using a variety of standard metrics and then apply SparseSignatures to whole genome sequences of pancreatic and breast tumors, discovering well-differentiated signatures that are linked to known mutagenic mechanisms.
Pervasive Transcription Fine-tunes Replication Origin Activity
Authors: Candelli Tito , Gros Julien , Libri Domenico 
Published: August 2018

ABSTRACTRNA polymerase (RNAPII) transcription occurs pervasively, which raises the important question of its functional impact on other DNA-associated processes, including replication. In budding yeast, replication originates from Autonomously Replicating Sequences (ARSs), generally located in intergenic regions. The influence of transcription on ARSs function has been studied for decades, but these earlier studies have necessarily neglected the role of non-annotated transcription. We studied the relationships between pervasive transcription and replication origin activity using high-resolution transcription maps. We show that ARSs alter the pervasive transcription landscape by pausing and terminating neighboring RNAPII transcription, thus limiting the occurrence of pervasive transcription within origins. We provide evidence that quasi-symmetrical binding of the ORC complex to ARS borders is responsible for pausing/termination. We also show that low, physiological levels of pervasive transcription impact the function of replication origins. Overall, our results have important implications for understanding the impact of genomic location on origin function.
Pathway-specific asymmetries between ON and OFF visual signals
Authors: Ravi Sneha , Ahn Daniel , Greschner Martin , Chichilnisky E.J , Field Greg D. 
Published: August 2018

AbstractVisual processing is largely organized into ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways exhibit natural pairings based on morphological and physiological similarities, such as ON and OFF alpha ganglion cells in the mammalian retina. Several studies have noted asymmetries in the properties of ON and OFF pathways. For example, the spatial receptive fields (RFs) of OFF alpha cells are systematically smaller than ON alpha cells. Analysis of natural scenes suggests these asymmetries are optimal for visual encoding. To test the generality of ON-OFF asymmetries, we measured the spatiotemporal RF properties of multiple RGC types in rat retina. Through a quantitative and serial classification, we identified three functional pairs of ON and OFF RGCs. We analyzed the structure of their RFs and compared spatial integration, temporal integration, and gain across ON and OFF pairs. Similar to previous results from cat and primate, RGC types with larger spatial RFs exhibited briefer temporal integration and higher gain. However, each pair of ON and OFF RGC types exhibited distinct asymmetric relationships between receptive field properties, some of which were opposite to previous reports. These results reveal the functional organization of six RGC types in the rodent retina and indicate that ON-OFF asymmetries are pathway specific.Significance StatementCircuits that process sensory input frequently process increments separately from decrements, so called ‘ON’ and ‘OFF’ responses. Theoretical studies indicate this separation, and associated asymmetries in ON and OFF pathways, may be beneficial for encoding natural stimuli. However, the generality of ON and OFF pathway asymmetries has not been tested. Here we compare the functional properties of three distinct pairs of ON and OFF pathways in the rodent retina and show their asymmetries are pathway specific. These results provide a new view on the partitioning of vision across diverse ON and OFF signaling pathways
Motor Learning Without Moving: Proprioceptive and Predictive Hand Localization After Passive Visuoproprioceptive Discrepancy Training
Authors: Mostafa Ahmed A. , ’t Hart Bernard Marius , Henriques Denise Y.P. 
Published: August 2018

AbstractAn accurate estimate of limb position is necessary for movement planning, before and after motor learning. Where we localize our unseen hand after a reach depends on felt hand position, or proprioception, but in studies and theories on motor adaptation this is quite often neglected in favour of predicted sensory consequences based on efference copies of motor commands. Both sources of information should contribute, so here we set out to further investigate how much of hand localization depends on proprioception and how much on predicted sensory consequences. We use a training paradigm combining robot controlled hand movements with rotated visual feedback that eliminates the possibility to update predicted sensory consequences (‘exposure training’), but still recalibrates proprioception, as well as a classic training paradigm with self-generated movements in another set of participants. After each kind of training we measure participants’ hand location estimates based on both efference-based predictions and afferent proprioceptive signals with self-generated hand movements (‘active localization’) as well as based on proprioception only with robot-generated movements (‘passive localization’). In the exposure training group, we find indistinguishable shifts in passive and active hand localization, but after classic training, active localization shifts more than passive, indicating a contribution from updated predicted sensory consequences. Both changes in open-loop reaches and hand localization are only slightly smaller after exposure training as compared to after classic training, confirming that proprioception plays a large role in estimating limb position and in planning movements, even after adaptation. (data: https://doi.org/10.17605/osf.io/zfdth, preprint: https://doi.org/10.1101/384941)
Condensin controls mitotic chromosome stiffness and stability without forming a structurally contiguous scaffold
Authors: Sun Mingxuan , Biggs Ronald , Hornick Jessica , Marko John F. 
Published: August 2018

AbstractDuring cell division, chromosomes must be folded into their compact mitotic form to ensure their segregation. This process is thought to be largely controlled by the action of condensin SMC protein complexes on chromatin fibers. However, how condensins organize metaphase chromosomes is not understood. We have combined micromanipulation of single human mitotic chromosomes, sub-nanonewton force measurement, siRNA interference of condensin subunit expression, and fluorescence microscopy, to analyze the role of condensin in large-scale chromosome organization. Condensin depletion leads to a dramatic (~10 fold) reduction in chromosome elastic stiffness relative to the native, non-depleted case. We also find that prolonged metaphase stalling of cells leads to overloading of chromosomes with condensin, with abnormally high chromosome stiffness. These results demonstrate that condensin is a main element controlling the stiffness of mitotic chromosomes. Isolated, slightly stretched chromosomes display a discontinuous condensing staining pattern, suggesting that condensins organize mitotic chromosomes by forming isolated compaction centers that do not form a continuous scaffold.
Brain peak width of skeletonised mean diffusivity (PSMD), processing speed, and other cognitive domains
Authors: Deary Ian J. , Ritchie Stuart J. , Maniega Susana Muñoz , Cox Simon R. , Hernández Maria C. Valdés , Starr John M. , Wardlaw Joanna M. , Bastin Mark E. 
Published: August 2018

AbstractIt is suggested that the brain’s peak width of skeletonised water mean diffusivity (PSMD) is a neuro-biomarker of processing speed, a crucial contributor to cognitive ageing. We tested whether PSMD is more strongly correlated with processing speed than with other cognitive domains, and more strongly than other structural brain MRI indices. Participants were 731 Lothian Birth Cohort 1936 members, mean age 73 years (SD=0.7); analytical sample was 656-680. Cognitive domains tested were: processing speed (5 tests), visuospatial (3), memory (3), and verbal (3). Brain-imaging variables included PSMD, white matter diffusion parameters and hyperintensity volumes, grey and white matter volumes, and perivascular spaces. PSMD was significantly associated with all processing speed tests; absolute standardised beta values were 0.11 to 0.23 (mean = 0.17). Other structural brain-imaging variables correlated as or more strongly. PSMD was significantly associated with processing speed (−0.27), visuospatial (−0.23), memory (−0.17), and general cognitive ability (−0.25). PSMD correlated with processing speed: but not more strongly than with other cognitive domains; and not more strongly than other brain-imaging measures.
Effects of the maternal factor Zelda on zygotic enhancer activity in theDrosophilaembryo
Authors: Li Xiao-Yong , Eisen Michael B. 
Published: August 2018

AbstractThe maternal factor Zelda is broadly bound to zygotic enhancers during early fly embryogenesis, and has been shown to be important for the expression of a large number of genes. However, its function remains poorly understood. Here, we carried out detailed analysis of the functional role of Zelda on the activities of a group of enhancers that drive patterned gene expression along the anterior -posterior axis. We found that among these enhancers, only one lost its activity entirely when all its Zelda bind sites were mutated. For all others, mutations of all of their Zelda binding sites only had limited effect, which varied temporally and spatially. These results suggest that Zld may exert a quantitative effect on a broad range of enhancers, which presumably is critical to generate highly diverse spatial and temporal expression patterns for different genes in the developmental gene network in fly embryo. Lastly, we found that the observed effect of Zelda site mutations was much stronger when a mutant enhancer was tested using a BAC based reporter construct than a simple reporter construct, suggesting that the effect of Zld is dependent on chromatin environment.
MyoviridaePhagePDXKills EnteroaggregativeEscherichia coliwithout Human Microbiome Dysbiosis
Authors: Cepko Leah C. S. , Garling Eliotte E. , Dinsdale Madeline J. , Scott William P. , Bandy Loralee , Nice Tim , Faber-Hammond Joshua , Mellies Jay L. 
Published: August 2018

AbstractPurposeTo identify therapeutic a bacteriophage that kills diarrheagenic enteroaggregativeEscherichia coli(EAEC) while leaving the human microbiome intact.MethodologyPhages from wastewater in Portland, OR, were screened for bacteriolytic activity using an overlay assay, and isolated in a sequential procedure to enrich for the recognition of core bacterial antigens. Electron microscopy and genome sequencing were performed to classify the isolated phage, and the host range was determined by spot tests and plaque assays. One-step growth curves and time-kill assays were conducted to characterize the life cycle of the phage, and to interrogate the multiplicity of infection (MOI) necessary for killing. A mouse model of infection was used to determine whether the phage could be used therapeutically against EAECin vivo. Anaerobic culture in the presence of human fecal bacteria determined whether the phage could kill EAECin vitro, and to assess whether the microbiome had been altered.ResultsThe isolated phage, termedEscherichia virus PDX, is a member of the strictly lyticMyoviridaefamily of viruses. PhagePDXkilled EAEC isolate EN1E-0227, a case-associated isolate from a child in rural Tennessee, in a dose-dependent manner, and also formed plaques on case-associated clinical EAEC isolates from Columbian children suffering from diarrhea. A single dose ofPDX, at a MOI of 100, one day post infection, reduced the population of recovered EAEC isolate EN1E-0227 bacteria in fecal pellets in a mouse model of colonization, over a five-day period. PhagePDXalso killed EAEC EN1E-0227 when cultured anaerobicallyin vitroin the presence of human fecal bacteria. While the addition of EAEC EN1E-0227 reduced the α-diversity of the human microbiota, that of the cultures with either feces alone, feces with EAEC andPDX, or with just thePDXphage were not different statistically, as measured by Chao1 and Shannon diversity indices. Additionally, β-diversity and differential abundance analyses show that conditions withPDXadded were not different from feces alone, but all groups were significantly different from feces + EAEC.ConclusionsThe strictly bacteriolytic,Myoviridae Escherichia virus PDXkilled EAEC isolate EN1E-0227 bacteria bothin vivoandin vitro, while simultaneously not altering the diversity of normal human microbiota in anaerobic culture. Thus, thePDXphage could be part of an effective therapeutic intervention for children in developing countries who suffer from acute, or persistent EAEC-mediated diarrhea, and to help reduce the serious effects of environmental enteropathy. Because the emerging pathogen EAEC is now the second leading cause of traveler’s diarrhea,PDXcould also provide therapeutic relief for these individuals, particularly in light of the growing crisis of antibiotic resistances.
Hessian single molecule localization microscopy using sCMOS camera
Authors: Xue Fudong , He Wenting , Xu Fan , Zhang Mingshu , Chen Liangyi , Xu Pingyong 
Published: August 2018

AbstractSingle-molecule localization microscopy (SMLM) has the highest spatial resolution among the existing super-resolution (SR) imaging techniques, but its temporal resolution needs further improvement. An sCMOS camera can effectively increase the imaging rate due to its large field of view and fast imaging speed. Using an sCMOS camera for SMLM imaging can significantly improve the imaging time resolution, but the unique single pixel-dependent readout noise of sCMOS cameras severely limits their application in SMLM imaging. This paper develops a Hessian-based SMLM (Hessian-SMLM) method that can correct the variance, gain and offset of a single pixel of a camera and effectively eliminate the pixel-dependent readout noise of sCMOS cameras, especially when the signal-to-noise ratio is low. Using Hessian SMLM to image mEos3.2-labeled actin was able to significantly reduce the artifacts due to camera noise.
Exogenous DCPTA ameliorates the soil drought effect on nitrogen metabolism in maize during the pre-female inflorescence emergence stage
Authors: Xie Tenglong , Gu Wanrong , Liguo Zhang , Li Congfeng , Li Wenhua , Wei Shi 
Published: August 2018

Abstract2-(3,4-Dichlorophenoxy) triethylamine (DCPTA) regulates many aspects of plant development; however, its effects on soil drought tolerance are unknown. We pre-treated maize (Zea mays L.) by foliar application of DCPTA and subsequently exposed the plants to soil drought and rewatering conditions during the pre-female inflorescence emergence stage. Exogenous DCPTA significantly alleviated drought-induced decreases in maize yield, shoot and root relative growth rate (RGR), leaf relative water content (RLWC), net photosynthetic rate (Pn), stomatal conductance (Gs) and transpiration rate (Tr), nitrate (NO3−), nitrite (NO2−), and soluble protein contents, and nitrate reductase (NR), nitrite reductase (NiR), isocitrate dehydrogenase (ICDH), alanine aminotransferase (AlaAT) and aspartate aminotransferase (AspAT) activities; increases in the intercellular CO2 concentration (Ci), the ammonium (NH4+) and free amino acid contents, and the glutamate dehydrogenase (GDH) and protease activities. Simultaneously, exogenous DCPTA improved the spatial and temporal distribution of roots and increased the root hydraulic conductivity (Lp), flow rate of root-bleeding sap and NO3− delivery rates. Moreover, Exogenous DCPTA protected the chloroplast structure from drought injury. Taken together, our results suggest that exogenous DCPTA mitigates the repressive effects of drought on N metabolism and subsequently enhances drought tolerance during the pre-female inflorescence emergence stage of maize.HighlightsThis is the first article that explores the effects of DCPTA on nitrogen metabolism and the first article that explores the effects of DCPTA on crops under soil drought conditions.
Actinic keratosis – review for clinical practice
Authors: de Oliveira Erika C. V. , da Motta Valéria R. V. , Pantoja Paola C. , Ilha Carolina S. de O. , Magalhães Renata F. , Galadari Hassan , Leonardi Gislaine R. 
Published: August 2018

AbstractActinic keratosis (AK) is a lesion that arises as a result of excessive exposure to solar radiation and appearing predominantly on Fitzpatrick phototype I and II skin. Given that some AKs evolve into squamous cell carcinoma, these lesions are considered premalignant in nature, occurring mostly in elderly men and immunosuppressed individuals chronically exposed to ultraviolet (UV) radiation. There are several mechanisms for the formation of AKs; among them are oxidative stress, immunosuppression, inflammation, altered proliferation and dysregulation of cell growth, impaired apoptosis, mutagenesis, and human papillomavirus (HPV). Through the understanding of these mechanisms, several treatments have emerged. Among the options for AK treatment, the most commonly used include 5‐fluorouracil (5‐FU), cryotherapy, diclofenac, photodynamic therapy (PDT), imiquimod (IQ), retinoids, and ingenol mebutate (IM). There have been recent advances in the treatment options that have seen the emergent use of newer agents such as resiquimod, betulinic acid, piroxicam, and dobesilate. The combination between therapies has presented relevant results with intention to reduce duration of therapy and side effects. All AK cases must be treated because of their propensity to transform into malignancy and further complicate treatment. In addition to medical or surgical care, education about sun exposure prevention remains the best and most cost‐effective method for AK prevention. The objective of this article is to conduct a literature review of the clinical presentation of AK including advances in treatment options available.
Risk factors for early and late procedure‐related adverse events in percutaneous endoscopic gastrostomy: A single center, retrospective study
Authors: Peveling‐Oberhag Jan , Osman Imad , Walter Dirk , Filmann Natalie , Stratmann Katharina , Hausmann Johannes , Knop Viola , Waidmann Oliver , Vermehren Johannes , Herrmann Eva , Zeuzem Stefan , Friedrich‐Rust Mireen , Blumenstein Irina , Albert Jörg G 
Published: August 2018

AbstractBackgroundPercutaneous endoscopic gastrostomy (PEG) provides the most common method to ensure enteral nutrition for various indications. However, PEG placement may be associated with relevant procedure‐related morbidity and mortality. We aimed to identify clinical parameters predicting an increased risk of PEG‐related adverse events.MethodsA retrospective analysis was performed for all patients who had undergone PEG placement in our center between August 2010 and January 2014. PEG‐related adverse events and risk factors were evaluated through review of endoscopic reports and medical charts. All patients were followed until death or study closure (median follow‐up 30 months, range 12–48).ResultsA total of 576 patients (417 male, mean age 56) were included. Indication for PEG insertion was preemptive or therapeutic in underlying oncological disease (n = 410), neurological diseases (n = 114), or others (n = 151). The pull method was used in 501 patients (87%). Overall, 56 (59%) and 39 (41%) patients had early (< 30 days) and late (> 30 days) adverse events of which 11.8% and 4.7% were classified as minor and major, respectively. Multivariate analysis showed that a high number of comorbidities, an oncological indication, and, as a statistical trend, high body mass index were associated with early adverse events. The use of the push method for insertion of PEG was associated with increased late adverse events, which mainly consisted of tube dislocations.ConclusionsClinical parameters that may easily be accessed correlate to an unfavorable outcome of a PEG procedure. This should raise the endoscopist's awareness for patients at high risk for adverse events.