bluuebunny/crossref_metadata_2025 huggingface dataset:
A genomic view of experimental intraspecies and interspecies transformation of a rifampicin-resistance allele into Neisseria meningitidis
Authors: Alfsnes Kristian , Frye Stephan A. , Eriksson Jens , Eldholm Vegard , Brynildsrud Ola Brønstad , Bohlin Jon , Harrison Odile B. , Hood Derek W. , Maiden Martin C. J. , Tønjum Tone , Ambur Ole Herman
Published: September 2018

The spread of antibiotic resistance within and between different bacterial populations is a major health problem on a global scale. The identification of genetic transformation in genomic data from Neisseria meningitidis, the meningococcus (Mc), and other bacteria is problematic, since similar or even identical alleles may be involved. A particular challenge in naturally transformable bacteria generally is to distinguish between common ancestry and true recombined sites in sampled genome sequences. Furthermore, the identification of recombination following experimental transformation of homologous alleles requires identifiable differences between donor and recipient, which in itself influences the propensity for homologous recombination (HR). This study identifies the distribution of HR events following intraspecies and interspecies Mc transformations of rpoB alleles encoding rifampicin resistance by whole-genome DNA sequencing and single nucleotide variant analysis. The HR events analysed were confined to the genomic region surrounding the single nucleotide genetic marker used for selection. An exponential length distribution of these recombined events was found, ranging from a few nucleotides to about 72 kb stretches. The lengths of imported sequences were on average found to be longer following experimental transformation of the recipient with genomic DNA from an intraspecies versus an interspecies donor (P<0.001). The recombination events were generally observed to be mosaic, with donor sequences interspersed with recipient sequence. Here, we present four models to explain these observations, by fragmentation of the transformed DNA, by interruptions of the recombination mechanism, by secondary recombination of endogenous self-DNA, or by repair/replication mechanisms.
Single Molecule Visualization of Cardiac Myosin-Binding Protein C N-terminal Fragments Interacting with Thin Filaments: Mechanisms of Calcium Sensitization
Authors: Inchingolo Alessio V. , Previs Samantha Beck , Previs Michael J. , Warshaw David M. , Kad Neil M.
Published: September 2018

Cardiac muscle contraction is activated by calcium binding to troponin and the consequent motion of tropomyosin on actin within the sarcomere. These movements permit myosin binding, filament sliding and motion generation. One potential mechanism by which the N-terminal domains of cardiac myosin-binding protein C (cMyBP-C) play a modulatory role in this activation process is by cMyBP-C binding directly to the actin-thin filament at low calcium levels to enhance the movement of tropomyosin. To determine the molecular mechanisms by which cMyBP-C enhances myosin recruitment to the actin-thin filament, we directly visualized fluorescently-labelled cMyBP-C N-terminal fragments and GFP-labelled myosin molecules binding to suspended actin-thin filaments in a fluorescence-based single molecule microscopy assay. Binding of the C0C3 N-terminal cMyBP-C fragment to the thin filament enhanced myosin association at low calcium levels. However, at high calcium levels, C0C3 bound cooperatively, blocking myosin binding. Dynamic imaging of thin filament-bound Cy3-C0C3 molecules demonstrated that these fragments diffuse along the thin filament before statically binding, suggesting a mechanism that utilizes a weak-binding mode to search for access to the thin filament and a tight-binding mode to sensitize the thin filament to calcium and thus, enhance myosin binding. Although shorter N-terminal fragments (Cy3-C0C1 and Cy3-C0C1f) bound to the thin filaments and displayed modes of motion on the thin filament similar to that of the Cy3-C0C3 fragment, the shorter fragments were unable to sensitize the thin filament. Therefore, the longer N-terminal fragment (C0C3) must possess the requisite domains needed to bind specifically to the thin filament in order for the cMyBP-C N terminus to modulate cardiac contractility.
Neurochemical correlates of scene processing in the precuneus/posterior cingulate cortex: a multimodal fMRI and 1H-MRS study
Authors: Costigan Alison G. , Umla-Runge Katja , Evans C. John , Hodgetts Carl J. , Lawrence Andrew D. , Graham Kim S.
Published: September 2018

Precuneus/posterior cingulate cortex (PCu/PCC) are key components of a midline network, activated during rest but also in tasks that involve construction of scene or situation models. Despite growing interest in PCu/PCC functional alterations in disease, the underlying neurochemical modulators of PCu/PCC’s task-induced activity are largely unstudied. Here, a multimodal imaging approach was applied to investigate whether inter-individual differences in PCu/PCC fMRI activity, elicited during perceptual discrimination of scene stimuli, were correlated with local brain metabolite levels, measured during resting-state 1H-MRS. Forty healthy young adult participants (12 male) completed an fMRI perceptual odd-one-out task for scenes, objects and faces. 1H-MRS metabolites N-acetyl-aspartate (tNAA), glutamate (Glx) and γ-amino-butyric acid (GABA+) were quantified via PRESS and MEGA-PRESS scans in a PCu/PCC voxel and an occipital (OCC) control voxel. Whole brain fMRI revealed a cluster in right dorsal PCu/PCC that showed a greater BOLD response to scenes versus faces and objects. When extracted from an independently defined PCu/PCC region of interest, scene activity (versus faces and objects and also versus baseline) was positively correlated with PCu/PCC, but not OCC, tNAA. A complementary fMRI analysis restricted to the PCu/PCC MRS voxel area identified a significant PCu/PCC cluster, confirming the positive correlation between scene-related BOLD activity and PCu/PCC tNAA. There were no correlations between PCu/PCC fMRI activity and Glx or GABA+ levels. These results demonstrate, for the first time, that scene activity in PCu/PCC is linked to local tNAA levels, identifying a neurochemical influence on inter-individual differences in the task-driven activity of a key brain hub.
Streptococcus salivarius - a potential salivary biomarker for orofacial granulomatosis and Crohn’s disease?
Authors: Goel Rishi M. , Prosdocimi Erica M. , Amar Ariella , Omar Yasmin , Escudier Michael P. , Sanderson Jeremy D. , Wade William G. , Prescott Natalie J.
Published: September 2018

Objective

Orofacial granulomatosis (OFG) is a rare disease characterised by chronic, non-caseating, granulomatous inflammation primarily affecting the oral cavity. Histologically, it is similar to Crohn’s disease (CD) and a proportion of patients have both OFG and CD. The cause of OFG remains elusive but it has been suggested that microbial interactions may be involved. The aim of this study was to compare the salivary microbial composition of subjects with OFG and/or CD and healthy controls.

Design

261 subjects were recruited, of whom 78 had OFG only, 40 had both OFG and CD, 97 had CD only with no oral symptoms and 46 were healthy controls. Bacterial community profiles were obtained by sequencing the V1-V3 region of the 16S rRNA gene.

Results

There were no differences in richness or diversity of the salivary bacterial communities between patient groups and controls. The relative abundance of the Streptococcus salivarius-group were raised in patients with OFG or CD only compared to controls while that of the Streptococcus mitis -group was lower in CD compared to both OFG and controls. One S. salivarius oligotype made the major contribution to the increased proportions seen in patients with OFG and CD.

Conclusion

The salivary microbiome of individuals with OFG and CD was similar to that found in health although the proportions of S. salivarius, a common oral Streptococcus were raised. One specific strain-level oligotype was found to be primarily responsible for the increased levels seen.
Accurate estimation of microbial diversity with Distanced
Authors: Hackmann Timothy J.
Published: September 2018

Microbes are the most diverse organisms on Earth. Sequencing their DNA suggests thousands of different microbes could be present in a single sample. Errors in sequencing, however, make it challenging to estimate exactly how diverse microbes are. Here we developed a tool that estimates diversity accurately, even in the presence of sequencing errors. We first evaluated two existing tools, DADA2 and Deblur, which work by correcting sequencing errors. We found that these tools estimated within-sample (alpha) diversity poorly. In fact, we obtained better estimates if did not use the tools at all (left errors uncorrected). These tools performed poorly because they changed the relative abundance of different sequences; this is a side effect of correcting errors and discarding up to 90% of sequence reads in the process. Previous evaluations ignored sequence abundance when calculating diversity, overlooking this problem. Our tool, Distanced, differs from existing tools because it does not correct sequencing errors. Instead, it corrects sequence distances, which are used to calculate diversity. It does this correction with Phred quality scores and Bayes theorem. No sequence reads are discarded in the process. In our evaluation, Distanced accurately estimated diversity of bacterial DNA, fungal DNA, and even antibody mRNA. Given its accuracy, Distanced will help investigators answer important questions about microbial diversity. For example, it could answer how important is diversity for the planets ecosystems and human health.
A Cortico-Basal Ganglia Model for choosing an optimal rehabilitation strategy in Hemiparetic Stroke
Authors: Narayanamurthy Rukhmani , Jayakumar Samyukta , Elango Sundari , Muralidharan Vignesh , Chakravarthy V. Srinivasa
Published: September 2018

To facilitate the selection of an optimal therapy for a stroke patient with upper extremity hemiparesis, we propose a cortico-basal ganglia model capable of performing reaching tasks under normal and stroke conditions. The model contains two hemispherical systems, each organized into an outer sensory-motor cortical loop and an inner basal ganglia (BG) loop, controlling their respective hands. In addition to constraint induced movement therapy (CIMT), the model performs both unimanual and bimanual reaching tasks and the simulation results are in congruence with the experiment conducted by Rose et al (2004). Based on our study on the effect of lesion size on arm performance, we hypothesize that the effectiveness of a therapy could greatly depend on this factor. By virtue of the model’s ability to capture the experimental results effectively, we believe that it can serve as a benchmark for the development and testing of various rehabilitation strategies for stroke.
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

In 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

Many 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

Spectral-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

Background and aims

Lactulose 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.

Methods

32 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.

Results

Lactulose 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.

Conclusion

Ingestion 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

Insect 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

The 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

Signal 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

Rapid, 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

Ultraviolet 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

Lineage-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

IFNγ 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

In 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.

Importance

Microbial 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

Stomatal 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.
Transient patterns of functional dysconnectivity in youth with psychosis spectrum symptoms
Authors: Mennigen Eva , Jolles Dietsje D. , Hegarty Catherine E. , Gupta Mohan , Jalbrzikowski Maria , Olde Loohuis Loes M. , Ophoff Roel A. , Karlsgodt Katherine H. , Bearden Carrie E.
Published: September 2018

Psychosis spectrum disorders are conceptualized as neurodevelopmental disorders accompanied by disruption of large-scale functional brain networks. Both static and dynamic dysconnectivity have been described in patients with schizophrenia and, more recently, in help-seeking individuals at clinical high-risk for psychosis. Less is known, however, about developmental aspects of dynamic functional network connectivity (FNC) associated with psychotic symptoms (PS) in the general population. Here, we investigate resting state fMRI data using established dynamic FNC methods in the Philadelphia Neurodevelopmental Cohort (ages 8-22), including 129 participants experiencing PS and 452 participants without PS (non-PS).

Applying a sliding window approach and k-means clustering, 5 dynamic states with distinct whole-brain connectivity patterns were identified. PS-associated dysconnectivity was most prominent in states characterized by synchronization or antagonism of the default mode network (DMN) and cognitive control (CC) domains. Hyperconnectivity between DMN, salience, and CC domains in PS youth only occurred in a state characterized by synchronization of the DMN and CC domains, a state that also becomes less frequent with age. However, dysconnectivity of the sensorimotor and visual systems in PS youth was revealed in other transient states completing the picture of whole-brain dysconnectivity patterns associated with PS.

Overall, state-dependent dysconnectivity was observed in PS youth, providing the first evidence that disruptions of dynamic functional connectivity are present across a broader psychosis continuum.
Long-range inhibitory intersection of a retrosplenial thalamocortical circuit by apical tuft-targeting CA1 neurons
Authors: Yamawaki Naoki , Li Xiaojian , Lambot Laurie , Ren Lynn Y. , Radulovic Jelena , Shepherd Gordon M. G.
Published: September 2018

Dorsal hippocampus, retrosplenial cortex (RSC), and anterior thalamic nuclei (ATN) interact to mediate diverse cognitive functions, but the cellular basis for these interactions is unclear. We hypothesized a long-range circuit converging in layer 1 (L1) of RSC, based on the pathway anatomy of GABAergic CA1 retrosplenial-projecting (CA1-RP) neurons and thalamo-restrosplenial projections from ATN. We find that CA1→RSC projections stem from GABAergic neurons with a distinct morphology, electrophysiology, and molecular profile, likely corresponding to recently described Ntng1-expressing hippocampal interneurons. CA1-RP neurons monosynaptically inhibit L5 pyramidal neurons, principal outputs of RSC, via potent GABAergic synapses onto apical tuft dendrites in L1. These inhibitory inputs align precisely with L1-targeting thalamocortical excitatory inputs from ATN, particularly the anteroventral nucleus, forming a convergent circuit whereby CA1 inhibition can intercept ATN excitation to co-regulate RSC activity. Excitatory axons from subiculum, in contrast, innervate proximal dendrites in deeper layers. Short-term synaptic plasticity differs at each connection. Chemogenetically abrogating inhibitory CA1→RSC or excitatory ATN→RSC connections oppositely affects the encoding of contextual fear memory. Collectively, our findings identify multiple cellular mechanisms underlying hippocampo-thalamo-retrosplenial interactions, establishing CA1 RSC-projecting neurons as a distinct class with long-range axons that target apical tuft dendrites, and delineating an unusual cortical circuit in the RSC specialized for integrating long-range inhibition and thalamocortical excitation.
Retinoblastoma binding protein 4 maintains cycling neural stem cells and prevents DNA damage and Tp53-dependent apoptosis in rb1 mutant neural progenitors
Authors: Schultz-Rogers Laura E. , Almeida Maira P. , Wierson Wesley A. , Kool Marcel , McGrail Maura
Published: September 2018

Retinoblastoma-binding protein 4 (Rbbp4) is a WDR adaptor protein for multiple chromatin remodelers implicated in human oncogenesis. Here we show Rbbp4 is overexpressed in zebrafish rb1-embryonal brain tumors and is upregulated across the spectrum of human embryonal and glial brain cancers. We demonstrate in vivo Rbbp4 is essential for zebrafish neurogenesis and has distinct roles in neural stem and progenitor cells. rbbp4 mutant neural stem cells show delayed cell cycle progression and become hypertrophic. In contrast, rbbp4 mutant neural precursors accumulate extensive DNA damage and undergo programmed cell death that is dependent on Tp53 signaling. Loss of Rbbp4 and disruption of genome integrity correlates with failure of neural precursors to initiate quiescence and transition to differentiation. rbbp4; rb1 double mutants show that survival of neural precursors after disruption of Rb1 is dependent on Rbbp4. Elevated Rbbp4 in Rb1-deficient brain tumors might drive proliferation and circumvent DNA damage and Tp53-dependent apoptosis, lending support to current interest in Rbbp4 as a potential druggable target.

Author Summary

Examining the developmental mechanisms controlling neural stem and progenitor cell behavior is critical to our understanding of the processes driving brain tumor oncogenesis. Chromatin remodelers and their associated adaptor proteins are thought to be key drivers of brain development and disease through epigenetic regulation of gene expression and maintenance of genome integrity, but knowledge of their in vivo roles in vertebrate neurogenesis is limited. The chromatin remodeler adaptor protein Rbbp4 has recently been shown to function in a mouse model of neuroblastoma and in glioblastoma multiforme cell resistance to the chemotherapeutic temozolomide. However, an in vivo requirement for Rbbp4 in neurogenesis has only just been shown by isolation of a recessive lethal mutation in zebrafish rbbp4. Here we provide conclusive genetic evidence that zebrafish rbbp4 is essential in neural stem and progenitor cell function during development. Our data reveal for the first time in vivo that Rbbp4 prevents DNA damage and activation of Tp53 signaling pathway that leads to programmed cell death. Importantly, neural progenitors that are mutant for the tumor suppressor Rb1 also depend on Rbbp4 for survival. Finally, we show that neural stem cells that have lost Rbbp4 cease dividing, and may enter a senescent like state. Together, these observations provide novel evidence that elevated expression of Rbbp4 in rb1-mutant tumors may contribute to cancer cell survival by blocking senescence and/or DNA damage-induced cell death.
Crystal structure and Hirshfeld surface analysis of 1,2-bis(2′,6′-diisopropoxy-[2,3′-bipyridin]-6-yl)benzene
Authors: Park Ki-Min , Moon Suk-Hee , Kang Youngjin
Published: September 2018

The title molecule, C38H42N4O4, displays a helical structure induced by the combination of the C—C—C—C torsion angle [−10.8 (2)°] between two 2,3′-bipyridyl units attached to the 1,2-positions of the central benzene ring and consecutive connections between five aromatic rings through the meta- and ortho-positions. Intramolecular C—H...π interactions between an H atom of a pyridine ring and the centroid of a another pyridine ring contributes to the stabilization of the helical structure. In the crystal, weak C—H...π interactions link the title molecules into a two-dimensional supramolecular network extending parallel to the ac plane, in which the molecules with right- and left-handed helical structures are alternately arranged. Hirshfeld surface analysis and two-dimensional fingerprint plots indicate that the molecular packing is dominated by van der Waals interactions between neighbouring H atoms, as well as by C—H...π interactions. One isopropoxyl group is disordered over two sets of sites [occupancy ratio 0.715 (5):0.285 (5)].
Encapsulated dichloroethane-mediated interlocked supramolecular polymeric assembly of A1/A2-dihydroxy-octyloxy pillar[5]arene 1,2-dichloroethane monosolvate
Authors: Al-Azemi Talal F. , Vinodh Mickey , Mohamod Abdirahman A. , Alipour Fatemeh H.
Published: September 2018

Crystals of 1-(1,4-dihydroxy)-2,3,4,5-(1,4-dioctyloxy)-pillar[5]arene, C99H158O10·C2H4Cl2, were grown from a 1,2-dicholoroethane/n-hexane solvent system. In the crystal, the encapsulated 1,2-dichloroethane solvent is stabilized by C—H...π interactions and mediates the formation of an interlocked supramolecular polymer via C—H...Cl interactions.
It’s about how employees feel! examining the impact of emotional culture on employee–organization relationships
Authors: Men Linjuan Rita , Robinson Katy L.
Published: September 2018

Purpose

The purpose of this paper is to examine the impact of emotional culture on the quality of employee–organization relationships (EORs). To understand the nuances of the influence of positive and negative emotional cultures on employee relational outcomes, this study specifically examined four fundamental emotional cultures, namely, joy, love, fear and sadness, in the cultivation of EORs. Further, as more recent emotional connotations of culture delve into the connections between employees’ fundamental need for psychological satisfaction and business success, likewise, this study proposes employees’ psychological need satisfaction as a potential mediator that explains how emotional culture influences employee–organization relational outcomes.

Design/methodology/approach

To test the hypothesized model, the authors conducted an online survey on a random sample of 509 employees working in 19 diverse industry sectors in a one-week period in February 2017, with the assistance of a premier global provider of survey services, Survey Sampling International. To test the hypothesized model, structural equation modeling analysis was employed using AMOS 24.0 software.

Findings

Results indicated that joy, happiness, excitement, companionate love, affection and warmth could meet employees’ psychological need for mutual respect, care, connection and interdependence within the organization. Such culture contributed to employees’ feelings of trust, satisfaction, mutual control and commitment toward the organization. By contrast, employees in organizations with a dispirited, downcast and sad emotional culture were less inclined to develop quality relationships with the organization. Employees in organizations where the emotional culture was fearful, anxious, tense or scared were less likely to satisfy their psychological need for relatedness.

Originality/value

This study is among one of the earliest attempts to theorize and operationalize organizational emotional culture, which fills the research gap in decades of organizational culture research that focused predominantly on the cognitive aspect. Also, this study expands the thriving relationship management literature, in particular, employee relationship management research by showing the positive impact of emotional culture of joy and love and negative impact of emotional culture of sadness on employee relational outcomes.
Impact of benevolent leadership on follower taking charge
Authors: Xu Qin , Zhao Yixuan , Xi Meng , Zhao Shuming
Published: September 2018

Purpose

The topic of employees’ taking charge behaviors has garnered increasing interest in both practical and academic fields. Leaders play a critical role in influencing followers’ taking charge behaviors, yet few studies have explored the predicting role of benevolent leadership. Drawing from proactive motivation literature, this paper aims to investigate a moderated mediation model that examines work engagement as the mediator and role-breadth self-efficacy as the moderator in the relationship between benevolent leadership and taking charge.

Design/methodology/approach

Matched data were collected from 297 followers and their group leaders in three subsidiaries of a large telecommunication company in China. The authors used hierarchical linear modeling to test the hypotheses.

Findings

The results revealed that benevolent leadership was positively related to followers’ work engagement and consequently their taking charge behaviors. Moreover, such moderated mediation relationship was stronger among followers who had low rather than high levels of role-breadth self-efficacy.

Research limitations/implications

The primary contribution of this study is building a contingent model for the effect of benevolent leadership on follower taking charge and thereby extending the nomological networks of both benevolent leadership and taking charge literatures. Another contribution is that this research provides a new perspective to understand how leadership leads to followers’ taking charge behaviors.

Originality/value

This is the first study to investigate how and when benevolent leadership predicts follower taking charge.