bluuebunny/crossref_metadata_2025_split huggingface dataset:
A specific Ret receptor isoform is required for pioneer axon outgrowth and growth cone dynamics
Authors: Tuttle Adam M. , Drerup Catherine M. , Marra Molly H. , Nechiporuk Alex V. 
Published: September 2018

AbstractIn many cases, axon growth and guidance are driven by pioneer axons, the first axons to grow in a particular region. Despite their dynamic pathfinding capabilities and developmental importance, there are very few pioneer neuron specific markers and thus theirin vivoidentification and functional interrogation have been difficult. We found that a Ret receptor isoform, Ret51, is highly enriched in peripheral sensory pioneer neurons and is required for pioneer axon outgrowth.Retnull mutant pioneer neurons differentiate normally; however, they displayed defects in growth cone morphology and formation of filopodia before pioneer axon extension prematurely halts. We also demonstrate loss-of-function of a retrograde cargo adaptor, JNK-interacting protein 3 (Jip3), phenocopied many of these axonal defects. We further found that loss of Jip3 led to accumulation of activated Ret receptor in pioneer growth cones, indicating a failure in the clearance of activated Ret from growth cones. Using an axon sever approach as well asin vivoanalysis of axonal transport, we showed Jip3 specifically mediates retrograde, but not anterograde, transport of activated Ret51. Finally, live imaging revealed that Jip3 and Ret51 were retrogradely co-transported in pioneer axons, suggesting Jip3 functions as an adapter for retrograde transport of Ret51. Taken together, these results identify Ret51 as a molecular marker of pioneer neurons and elucidate an important isoform-specific role for Ret51 in axon growth and growth cone dynamics during development.
Morning and Evening Circadian Pacemakers Independently Drive Premotor Centers via a Specific Dopamine Relay
Authors: Liang Xitong , Ho Margaret C.W. , Wu Mark N. , Holy Timothy E. , Taghert Paul H. 
Published: September 2018

AbstractMany animals exhibit morning and evening peaks of locomotor behavior. In Drosophila, previous studies identified two corresponding circadian neural oscillators: M (morning) cells which exhixbit a morning neural activity peak, and E (evening) cells which exhibit a corresponding evening peak of activity. Yet we know little of how these distinct circadian oscillators produce specific outputs that regulate pre-motor circuits to precisely control behavioral episodes. Here we show that the Ring Neurons of the Ellipsoid Body (EB-RNs), a defined pre-motor center, display a spontaneous in vivo neural activity rhythm, with peaks in the morning and in the evening. The two EB-RN activity peaks coincide with the major bouts of locomotor activity and result from independent activation by M and E cells, respectively. Further, M and E cells regulate EB-RNs via two identified dopaminergic neurons PPM3-EB, which project to the EB and which are normally co-active with EB-RNs. Blocking the dopaminergic modulation onto EB-RNs prevents the daily two-peak pattern of neural activity in the EB-RN and greatly impairs circadian locomotor activity. These in vivo findings establish the fundamental elements of a circadian neuronal output pathway: distinct circadian oscillators independently drive a common pre-motor center through the agency of specific dopaminergic interneurons.
Automated Summarisation of SDOCT Volumes using Deep Learning: Transfer Learning vs de novo Trained Networks
Authors: Antony Bhavna J. , Maetschke Stefan , Garnavi Rahil 
Published: September 2018

AbstractSpectral-domain optical coherence tomography (SDOCT) is a non-invasive imaging modality that generates high-resolution volumetric images. This modality finds widespread usage in ophthalmology for the diagnosis and management of various ocular conditions. The volumes generated can contain 200 or more B-scans. Manual inspection of such large quantity of scans is time consuming and error prone in most clinical settings. Here, we present a method for the generation of visual summaries of SDOCT volumes, wherein a small set of B-scans that highlight the most clinically relevant features in a volume are extracted. The method was trained and evaluated on data acquired from age-related macular degeneration patients, and “relevance” was defined as the presence of visibly discernible structural abnormalities. The summarisation system consists of a detection module, where relevant B-scans are extracted from the volume, and a set of rules that determines which B-scans are included in the visual summary. Two deep learning approaches are presented and compared for the classification of B-scans - transfer learning and de novo learning. Both approaches performed comparably with AUCs of 0.97 and 0.96, respectively, obtained on an independent test set. The de novo network, however, was 98% smaller than the transfer learning approach, and had a run-time that was also significantly shorter.
Microbiota stability in healthy individuals after single-dose lactulose challenge – a randomized controlled study
Authors: Wotzka Sandra Y. , Kreuzer Markus , Maier Lisa , Zünd Mirjam , Schlumberger Markus , Nguyen Bidong , Fox Mark , Pohl Daniel , Heinrich Henriette , Rogler Gerhard , Biedermann Luc , Scharl Michael , Sunagawa Shinichi , Hardt Wolf-Dietrich , Misselwitz Benjamin 
Published: September 2018

AbstractBackground and aimsLactulose is a common food ingredient and widely used as a treatment for constipation or hepatic encephalopathy and a substrate for hydrogen breath tests. Lactulose is fermented by the colon microbiota resulting in the production of hydrogen (H2). H2is a substrate for enteropathogens includingSalmonellaTyphimurium (S. Typhimurium) and increased H2production upon lactulose ingestion might favor the growth of H2-consuming enteropathogens. We aimed to analyze effects of single-dose lactulose ingestion on the growth of intrinsicEscherichia coli(E. coli), which can be efficiently quantified by plating and which share most metabolic requirements withS. Typhimurium.Methods32 healthy volunteers (18 females, 14 males) were recruited. Participants were randomized for single-dose ingestion of 50 g lactulose or 50 g sucrose (controls). After ingestion, H2in expiratory air and symptoms were recorded. Stool samples were acquired at days −1, 1 and 14. We analyzed 16S microbiota composition and abundance and characteristics ofE.coliisolates.ResultsLactulose ingestion resulted in diarrhea in 14/17 individuals. In 14/17 individuals, H2-levels in expiratory air increased by ≥20 ppm within 3 hours after lactulose challenge. H2-levels correlated with the number of defecations within 6 hours.E. coliwas detectable in feces of all subjects (2 x 102- 109CFU/g). However, the number ofE.colicolony forming units (CFU) on selective media did not differ between any time point before or after challenge with sucrose or lactulose. The microbiota composition also remained stable upon lactulose exposure.ConclusionIngestion of a single dose of 50 g lactulose does not significantly alterE.colidensity in stool samples of healthy volunteers. 50 g lactulose therefore seems unlikely to sufficiently alter growth conditions in the intestine for a significant predisposition to infection with H2-consuming enteropathogens such asS. Typhimurium (www.clinicaltrials.govNCT02397512).
Complex responses of global insect pests to climate change
Authors: Lehmann Philipp , Ammunét Tea , Barton Madeleine , Battisti Andrea , Eigenbrode Sanford D. , Jepsen Jane Uhd , Kalinkat Gregor , Neuvonen Seppo , Niemelä Pekka , Økland Bjørn , Terblanche John S. , Björkman Christer 
Published: September 2018

AbstractInsect pests strongly affect the productivity and profitability of agriculture and forestry. Despite the well-known sensitivity of insects to abiotic effects such as temperature, their potential responses to ongoing climate change remain unclear. Here we compile and review documented climate change responses of 31 of the globally most impactful phytophagous insect pests, focussing on species for which long-term, high-quality data are available. Most of the selected species show at least one response affecting their severity as pests, including changes in geographic range, population dynamics, life-history traits, and/or trophic interactions. Of the studied pests, 41% only show responses that are linked to increased pest severity, 4% only show responses of decreased severity, whereas importantly 55%, the majority of studied pests, show mixed responses including both increased and decreased severity under ongoing climate change. Variability in impact is further supported by a thermal sensitivity analysis showing little benefit of climate warming in relation to the optimal developmental temperatures for the majority of these pests under both current climate and future projections. Overall the results show that calculating the net effect of climate change on phytophagous insect pest impact is far from straightforward. The documented variation in responses, e.g. between agricultural and forest pests, indicates that efforts to mitigate undesirable climate change effects must target individual species, taking into account the complex ecological and evolutionary mechanisms underlying their responses.
Chronology-based architecture of descending circuits that underlie the development of locomotor repertoire after birth
Authors: Pujala Avinash , Koyama Minoru 
Published: September 2018

AbstractThe emergence of new and increasingly sophisticated behaviors after birth is accompanied by dramatic increase of newly established synaptic connections in the nervous system. Little is known, however, of how nascent connections are organized to support such new behaviors alongside existing ones. To understand this, in the larval zebrafish we examined the development of spinal pathways from hindbrain V2a neurons and the role of these pathways in the development of locomotion. We found that new projections are continually layered laterally to existing neuropil, and give rise to distinct pathways that function in parallel to existing pathways. Across these chronologically layered pathways, the connectivity patterns and biophysical properties vary systematically to support a behavioral repertoire with a wide range of kinematics and dynamics. Such layering of new parallel circuits equipped with systematically changing properties may be central to the postnatal diversification and increasing sophistication of an animal’s behavioral repertoire.
Master regulators of signaling pathways coordinate key processes of embryonic development in breast cancer
Authors: Tapia-Carrillo Diana , Tovar Hugo , Velazquez-Caldelas Tadeo E. , Hernandez-Lemus Enrique 
Published: September 2018

AbstractSignal transduction pathways allow cells to respond to environmental cues and can induce intracellular changes. In some contexts, like embryonic development, signal transduction plays crucial roles in cell fate determination and differentiation, while in developed organisms some of this processes contribute in the maintenance of the structural integrity of tissues.Tumor cells are recognized as having deregulated signaling which leads to a series of abnormal behaviors known as the hallmarks of cancer. Although gene regulation is often viewed as the last step in signal transduction, transcriptional regulation of the components of a pathway may impact in the long term deregulation observed in tumors. The study of gene regulatory networks centered around genes of the signal transduction pathways allows the identification of transcriptional regulators with the greatest influence over the signal transduction gene signature, also denominated Master Regulators.In this work we identify, the master regulators that regulate the expression of genes of 25 relevant pathways grouped in KEGG within the category of signal transduction in a breast cancer dataset. For this purpose we implemented a modified MARINa algorithm that identifies, from a network of regulons, those that possess more differentially expressed genes related to the process to be studied. We identified CLOCK, TSHZ2, HOXA2, MEIS2, HOXA3, HAND2, HOXA5, TBX18, PEG3 and GLI2 as the top 10 master regulators of signaling pathways in breast cancer. Nine of them are recognized for taking part in embryonic development associated processes.Individual enrichment GO biological function for each TMR regulons showed to be significantly enriched in embryonic development related processes. Hedgehog signaling pathway was shown as enriched and also highly deregulated. The genes of the HOXA family are shared among most of the TMRs. Overall, this suggests the importance of the aberrant reprogramming of mechanisms present during embryonic development, being coopted in favor of tumor development.
DeepCDpred: Inter-residue Distance and Contact Prediction for Improved Prediction of Protein Structure
Authors: Ji Shuangxi , Oruç Tŭgçe , Mead Liam , Rehman Muhammad Fayyaz , Thomas Christopher M , Butterworth Sam , Winn Peter J 
Published: September 2018

AbstractRapid, accurate prediction of protein structure from amino acid sequence would accelerate fields as diverse as drug discovery, synthetic biology and disease diagnosis. Massively improved prediction of protein structures has been driven by improving the prediction of the amino acid residues that contact in their 3D structure. For an average globular protein, around 92% of all residue pairs are non-contacting, therefore accurate prediction of only a small percentage of inter-amino acid distances could increase the number of constraints to guide structure determination. We have trained deep neural networks to predict inter-residue contacts and distances. Distances are predicted with an accuracy better than most contact prediction techniques. Addition of distance constraints improved de novo structure predictions for test sets of 158 protein structures, as compared to using the best contact prediction methods alone. Importantly, usage of distance predictions allows the selection of better models from the structure pool without a need for an external model assessment tool. The results also indicate how the accuracy of distance prediction methods might be improved further.
Cell type-specific differences in redox regulation and proliferation after low UVA doses
Authors: Ciesielska Sylwia , Bil Patryk , Gajda Karolina , Poterala-Hejmo Aleksandra , Hudy Dorota , Rzeszowska-Wolny Joanna 
Published: September 2018

AbstractUltraviolet A (UVA) radiation is harmful for living organisms but in low doses may stimulate cell proliferation. Our aim was to examine the relationships between exposure to different low UVA doses, cellular proliferation, and changes in cellular reactive oxygen species levels. In human colon cancer (HCT116) and melanoma (Me45) cells exposed to UVA doses comparable to environmental, the highest doses (30-50 kJ/m2) reduced clonogenic potential but some lower doses (1 and 10 kJ/m2) induced proliferation. This effect was cell type and dose specific. In both cell lines the levels of reactive oxygen species and nitric oxide fluctuated with dynamics which were influenced differently by UVA; in Me45 cells decreased proliferation accompanied the changes in the dynamics of H2O2while in HCT116 cells those of superoxide. Genes coding for proteins engaged in redox systems were expressed differently in each cell line; transcripts for thioredoxin, peroxiredoxin and glutathione peroxidase showed higher expression in HCT116 cells whereas those for glutathione transferases and copper chaperone were more abundant in Me45 cells. We conclude that these two cell types utilize different pathways for regulating their redox status. Many mechanisms engaged in maintaining cellular redox balance have been described. Here we show that the different cellular responses to a stimulus such as a specific dose of UVA may be consequences of the use of different redox control pathways. Assays of superoxide and hydrogen peroxide level changes after exposure to UVA may clarify mechanisms of cellular redox regulation and help in understanding responses to stressing factors.
The Lineage-Specific Transcription Factor CDX2 Navigates Dynamic Chromatin to Control Distinct Stages of Intestine Development
Authors: Kumar Namit , Tsai Yu-Hwai , Chen Lei , Zhou Anbo , Banerjee Kushal K. , Saxena Madhurima , Huang Sha , Xing Jinchuan , Shivdasani Ramesh A. , Spence Jason R. , Verzi Michael P. 
Published: September 2018

AbstractLineage-restricted transcription factors, such as the intestine-specifying factor CDX2, often have dual requirements across developmental time. Embryonic-loss of CDX2 triggers homeotic transformation of intestinal fate, while adult-onsetCdx2-loss compromises critical physiological functions but preserves intestinal identity. It is unclear how such diverse requirements are executed across the developmental continuum. Using primary and engineered human tissues, mouse genetics, and a multi-omics approach, we demonstrate that divergent CDX2 loss-of-function phenotypes in embryonic versus adult intestines correspond to divergent CDX2 chromatin-binding profiles in embryonic versus adult stages. CDX2 binds and activates distinct target genes in developing versus adult mouse and human intestinal cells. We find that temporal shifts in chromatin accessibility correspond to these context-specific CDX2 activities. Thus, CDX2 is not sufficient to activate a mature intestinal program, but rather, CDX2 responds to its environment, targeting stage-specific genes to contribute to either intestinal patterning or maturity. This study provides insights into the mechanisms through which lineage-specific regulatory factors achieve divergent functions over developmental time.
Regulation of distinct STAT3 dynamics in pro (IFNγ) and anti (IL-10) inflammatory pathways and in their cross-talk: insights from a data-driven model
Authors: Sarma U , Maiti M , Nair A , Bhadange S , Srivastava A , Saha B , Mukherjee D 
Published: September 2018

AbstractIFNγ and IL10 pathways elicit functionally opposing cell fates, however, these two stimuli activate common transcription factors like STAT1 and STAT3 (S/1/3). How the two stimuli regulate the dynamics of S/1/3 activation remains less understood. Here, we experimentally measured the signaling dynamics of S/1/3 in response to IFNγ and IL10 and found that STAT3, in particular, exhibits a bell-shaped response to both stimuli with maximal activation in an intermediate dose. We built a mathematical model, which quantitatively captured the S/1/3 dynamics and by model analysis, we identified the primary regulators controlling the bell-shaped STAT3 responses in both pathways. As the STATs are activated in response to both stimuli, in a scenario when cells are subjected to co-stimulation of IFNγ and IL10, an interpathway competition to activate the common substrate is plausible. Additionally, a strong transcriptional induction of SOCS1 (a negative regulator of IFNγ pathway) was observed upon IL10 stimulation, suggesting that IL10 pathway can potentially inhibit the IFNγ pathway via SOCS1 induction. To quantitatively understand the S/1/3 responses to co-stimulation we next simulated the same which predicted STAT3 activation and SOCS1 induction dynamics would robustly remain IL10 driven. Subsequent experiments validated the model predictions. Further, the model analysis identified the primary regulators controlling the robustness of IL10-STAT3 axis in co-stimulation. Together, our data-driven model quantitatively captured the dynamics of the STATs in response to both pro (IFNγ) and anti (IL10)-inflammatory stimuli and identifies distinct regulatory elements controlling STAT3 signaling in individual and co-stimulation conditions.
Engineered inter-species amino acid cross-feeding increases population evenness in a synthetic bacterial consortium
Authors: Ziesack Marika , Gibson Travis , Oliver John K.W. , Shumaker Andrew M. , Hsu Bryan B. , Riglar David T. , Giessen Tobias W. , DiBenedetto Nicholas V. , Bry Lynn , Way Jeffrey C. , Silver Pamela A. , Gerber Georg K. 
Published: September 2018

AbstractIn nature, microbes interact antagonistically, neutrally or beneficially. To shed light on the effects of positive interactions in microbial consortia we introduced metabolic dependencies and metabolite overproduction into four bacterial species. While antagonistic interactions govern the wildtype consortium behavior, the genetic modifications alleviated antagonistic interactions and resulted in beneficial interactions. Engineered cross-feeding increased population evenness, a component of ecological diversity, in different environments including in a more complex gnotobiotic mouse gut environment. Our findings suggest that metabolite cross-feeding could be used as a tool for intentionally shaping microbial consortia in complex environments.ImportanceMicrobial communities are ubiquitous in nature. Bacterial consortia live in and on our body and in our environment and more recently, biotechnology is applying microbial consortia for bioproduction. As part of our body, bacterial consortia influence us in health and disease. Microbial consortia function is determined by its composition, which in turn is driven by the interactions between species. Further understanding of microbial interactions will help us deciphering how consortia function in complex environments and may enable us to modify microbial consortia for health and environmental benefits.
Environment and HSP90 modulate MAPK stomatal developmental pathway
Authors: Samakovli Despina , Tichá Tereza , Ovečka Miroslav , Luptovčiak Ivan , Zapletalová Veronika , Krasylenko Yuliya , Komis George , Šamajová Olga , Margaritopoulou Theoni , Roka Loukia , Milioni Dimitra , Hatzopoulos Polydefkis , Šamaj Jozef 
Published: September 2018

ABSTRACTStomatal ontogenesis is a key element of plant adaptation aiming to control photosynthetic efficiency and water management under fluctuating environments 1,2,3. Development of stomata is guided by endogenous and environmental cues and is tightly coupled to overall plant growth 1,2,3. YODA signaling pathway is essential to stomatal lineage specification4,5,6 since it regulates the activities of transcription factors such as SPEECHLESS (SPCH)7,8,9,10. Heat-shock proteins 90 (HSP90s) are evolutionarily conserved molecular chaperones implicated in a broad range of signalling pathways being integrated in interaction networks with client proteins11,12,13,14. Herein, based on genetic, molecular, biochemical, and cell biological evidence we report that heat-stress conditions affect phosphorylation and deactivation of SPCH and modulate stomatal density. We show that genetic and physical interactions between HSP90s and YODA control stomatal patterning, distribution and morphology. We provide solid evidence that HSP90s play a major role in transducing the heat-stress response since they act upstream and downstream of YODA signalling, regulate the activity and nucleocytoplasmic distribution of MAPKs, and the activation of SPCH. Thus, HSPs control the stomatal development both under normal temperature and acute heat-stress conditions. Our results demonstrate that HSP90s couple stomatal formation and patterning to environmental cues providing an adaptive mechanism of heat-stress tolerance response and stomatal formation in Arabidopsis.