bluuebunny/crossref_metadata_2025 huggingface dataset:
Presenting and sharing clinical data using the eTRIKS Standards Master Tree for tranSMART
Authors: Barbosa-Silva Adriano , Bratfalean Dorina , Gu Wei , Satagopam Venkata , Houston Paul , Becnel Lauren B , Eifes Serge , Richard Fabien , Tielmann Andreas , Herzinger Sascha , Rege Kavita , Balling Rudi , Peeters Paul , Schneider Reinhard
Published: September 2018

Motivation

Standardization and semantic alignment have been considered one of the major challenges for data integration in clinical research. The inclusion of the CDISC SDTM clinical data standard into the tranSMART i2b2 via a guiding master ontology tree positively impacts and supports the efficacy of data sharing, visualization and exploration across datasets.

Results

We present here a schema for the organization of SDTM variables into the tranSMART i2b2 tree along with a script and test dataset to exemplify the mapping strategy. The eTRIKS master tree concept is demonstrated by making use of fictitious data generated for four patients, including 16 SDTM clinical domains. We describe how the usage of correct visit names and data labels can help to integrate multiple readouts per patient and avoid ETL crashes when running a tranSMART loading routine.

Availability and implementation

The eTRIKS Master Tree package and test datasets are publicly available at https://doi.org/10.5281/zenodo.1009098 and a functional demo installation at https://public.etriks.org/transmart/datasetExplorer/ under eTRIKS—Master Tree branch, where the discussed examples can be visualized.
De novopattern discovery enables robust assessment of functional consequences of non-coding variants
Authors: Yang Hai , Chen Rui , Wang Quan , Wei Qiang , Ji Ying , Zheng Guangze , Zhong Xue , Cox Nancy J , Li Bingshan
Published: September 2018

Motivation

Given the complexity of genome regions, prioritize the functional effects of non-coding variants remains a challenge. Although several frameworks have been proposed for the evaluation of the functionality of non-coding variants, most of them used ‘black boxes’ methods that simplify the task as the pathogenicity/benign classification problem, which ignores the distinct regulatory mechanisms of variants and leads to less desirable performance. In this study, we developed DVAR, an unsupervised framework that leverage various biochemical and evolutionary evidence to distinguish the gene regulatory categories of variants and assess their comprehensive functional impact simultaneously.

Results

DVAR performed de novo pattern discovery in high-dimensional data and identified five regulatory clusters of non-coding variants. Leveraging the new insights into the multiple functional patterns, it measures both the between-class and the within-class functional implication of the variants to achieve accurate prioritization. Compared to other two-class learning methods, it showed improved performance in identification of clinically significant variants, fine-mapped GWAS variants, eQTLs and expression-modulating variants. Moreover, it has superior performance on disease causal variants verified by genome-editing (like CRISPR-Cas9), which could provide a pre-selection strategy for genome-editing technologies across the whole genome. Finally, evaluated in BioVU and UK Biobank, two large-scale DNA biobanks linked to complete electronic health records, DVAR demonstrated its effectiveness in prioritizing non-coding variants associated with medical phenotypes.

Availability and implementation

The C++ and Python source codes, the pre-computed DVAR-cluster labels and DVAR-scores across the whole genome are available at https://www.vumc.org/cgg/dvar.

Supplementary information

Supplementary data are available at Bioinformatics online.
SemGen: a tool for semantics-based annotation and composition of biosimulation models
Authors: Neal Maxwell L , Thompson Christopher T , Kim Karam G , James Ryan C , Cook Daniel L , Carlson Brian E , Gennari John H
Published: September 2018

As the number and complexity of biosimulation models grows, so do demands for tools that can help users understand models and compose more comprehensive and accurate systems from existing models. SemGen is a tool for semantics-based annotation and composition of biosimulation models designed to address this demand. A key SemGen capability is to decompose and then integrate models across existing model exchange formats including SBML and CellML. To support this capability, we use semantic annotations to explicitly capture the underlying biological and physical meanings of the entities and processes that are modeled. SemGen leverages annotations to expose a model’s biological and computational architecture and to help automate model composition.

Availability and implementation

SemGen is freely available at https://github.com/SemBioProcess/SemGen.

Supplementary information

Supplementary data are available at Bioinformatics online.
Association of Circadian Rhythm of Blood Pressure and Cerebral Small Vessel Disease in Community-Based Elderly Population
Authors: Zhang Hua , Cui Yi , Zhao Yingxin , Dong Yuanli , Wang Juan , Duan Dandan , Ji Tiantian , Zhou Tingting , Hu Wenjing , Chen Yali , Sun Shangwen , Gong Gary , Chai Qiang , Liu Zhendong
Published: September 2018

Background

Although it is accepted that the etiology of cerebral small vessel disease (CSVD) is associated with cardiovascular risk factors, the association between CSVD and the circadian rhythm of blood pressure (BP) is unclear. We aimed to determine if such an association existed in the elderly population.

Method

White matter hyperintensities (WMHs), lacunes, microbleeds, nocturnal dipping pattern (NDP), and morning surge in systolic blood pressure (SBP) were assessed in 2,091 participants ≥60 years of age.

Results

During an average of 63 months of follow-up, WMH and the WMH-to-intracranial volume ratio were significantly increased in extreme dippers, nondippers, and reverse dippers than those in dippers (p < .001). For new-incident Fazekas scale ≥2, the hazard ratios were 1.77 (95% confidence interval [CI], 1.09–2.86) for extreme dippers, 2.20 (95% CI, 1.48–3.28) for nondippers, and 2.43 (95% CI, 1.59–3.70) for reverse dippers compared with dippers, and 1.04 (95% CI, 0.81–1.35) for higher morning surge compared with lower morning surge. Nondippers and reverse dippers were associated with higher risks of new-incident lacunes and microbleeds than dippers (p < .05). Higher morning surge was associated with a higher risk of new-incident microbleeds than lower morning surge (p < .05).

Conclusion

NDPs in SBP played an important role in CSVD, and the morning surge in SBP was associated with cerebral microbleeds in community-based elderly population beyond the average SBP level.
Synergistic Effects of Mesenchymal Stem Cell Transplantation and Repetitive Transcranial Magnetic Stimulation on Promoting Autophagy and Synaptic Plasticity in Vascular Dementia
Authors: Wang Fei , Zhang Chi , Hou Siyuan , Geng Xin
Published: September 2018

Repetitive transcranial magnetic stimulation (rTMS) and mesenchymal stem cells (MSCs) transplantation both showed therapeutic effects on cognition impairment in vascular dementia (VD) model rats. However, whether these two therapies have synergistic effects and the molecular mechanisms remain unclear. In our present study, rats were randomly divided into six groups: control group, sham operation group, VD group, MSC group, rTMS group, and MSC+rTMS group. The VD model rats were prepared using a modified 2VO method. rTMS treatment was implemented at a frequency of 5 Hz, the stimulation intensity for 0.5 Tesla, 20 strings every day with 10 pulses per string and six treatment courses. The results of the Morris water maze test showed that the learning and memory abilities of the MSC group, rTMS group, and MSC+rTMS group were better than that of the VD group, and the MSC+rTMS group showed the most significant effect. The protein expression levels of brain-derived neurotrophic factor, NR1, LC3-II, and Beclin-1 were the highest and p62 protein was the lowest in the MSC+rTMS group. Our findings demonstrated that rTMS could further enhance the effect of MSC transplantation on VD rats and provided an important basis for the combined application of MSC transplantation and rTMS to treat VD or other neurological diseases.
Systematic Conservation Planning
Authors: Baldwin Robert Fritz
Published: September 2018

The high rate of biodiversity loss due to human activities constitutes a sixth major extinction and is driven largely by habitat loss and fragmentation. An antidote is to carefully restitch the fabric by systematically prioritizing where new locations for conservation should be and building habitat corridors. Edward O. Wilson in his popular book Half Earth: Our Planet’s Fight for Life (see Wilson 2016, cited under The Reason for Planning: Nature in Pieces), argued that we need to manage as much as half of the planet for biodiversity and ecosystem services, bold thinking that has been followed with policy initiatives such as the 30 percent by 2030 initiatives in the United States and Europe. While the relative benefits of focusing on establishment of new protected areas versus improving the habitat quality in the human-dominated matrix are debated, we have better than ever tools and theoretical constructs to map where conservation investments should be made. Also increasing is the realization that a future in which biodiversity, including patterns and processes of change, is protected is impossible without the well-being of humans. Systematic conservation planning began as a field focused mainly on finding and setting aside combinations of places to protect biodiversity, and it has evolved to be inclusive of social, cultural, and economic conditions. Systematic conservation planning has its roots in biogeography, planning, and landscape ecology, which are rooted historically in European and Asian approaches to mapping landscapes. A field that began as an effort to understand the spatial patterns in nature, such as Alexander von Humboldt and Aimé Bonpland’s 1807 Essay on the Geography of Plants and N. A. Solnetsev’s 1948 exploration of Russian landscape features (urotshistshe), evolved over time to piecing back together nature’s parts. “Systematic Conservation Planning” in Nature (see Margules and Pressey 2000, cited under the Dynamic Field of Systematic Conservation Planning), urged systematically assessing the biological value of every area for its ability to represent ecological pattern and process in relation to its degree of threat and, hence, level of priority. Concurrently massive, global geospatial data gathering projects made mapping biodiversity at multiple scales more plausible. Numerous pieces of software for processing the complex tasks involved became available. Systematic conservation planning was critiqued as being tone deaf to human needs, which, in the poorer parts of the planet, often coincide with those of biodiversity. Today it’s far more intersectional, weighing combined ecological, social, and cultural factors.
Long-Lasting Primed State in Maize Plants: Salicylic Acid and Steroid Signaling Pathways as Key Players in the Early Activation of Immune Responses in Silks
Authors: Agostini Romina B , Postigo Agustina , Rius Sebastian P. , Rech Gabriel E. , Campos-Bermudez Valeria A. , Vargas Walter A.
Published: September 2018

In the present study, we investigated the induced systemic resistance (ISR) activated by the beneficial fungus Trichoderma atroviride in maize plants, and the early immunological responses triggered after challenge with the ear rot pathogen Fusarium verticillioides. By transcriptional analysis, we were able to identify the gene core set specifically modulated in silks of maize plants expressing ISR. Our results showed that the main transcriptional reprogramming falls into genes involved in five main functional categories: cell structure or cell wall, amino acid and protein metabolism, stress responses, signaling, and transport. Among these ISR-related genes, it is important to highlight novel findings regarding hormone metabolism and signaling. The expression of hormone-dependent genes was in good agreement with the abscisic acid, jasmonic acid, and salicylic acid (SA) levels detected in the plants under study. The experimental design allowed the identification of novel regulatory elements related to a heightened state of defense in silks and suggests that steroids and SA are central components of a master regulatory network controlling the immunity of silks during ISR. The results presented also provide evidence about the molecular mechanisms used by maize silks against F. verticillioides to counteract pathogenic development and host invasion, including pathogenesis-related genes, plant cell-wall reinforcement, fungal cell-wall-degrading enzymes and secondary metabolism.
Evaluation of a Sclerotinia homoeocarpa Population with Multiple Fungicide Resistance Phenotypes Under Differing Selection Pressures
Authors: Sang Hyunkyu , Popko James T. , Jung Geunhwa
Published: September 2018

Dollar spot, caused by Sclerotinia homoeocarpa, is one of the most significant diseases of cool-season turfgrass on golf courses. Resistance to the benzimidazole, dicarboximide, and succinate dehydrogenase inhibitor (SDHI) classes and reduced sensitivity to the sterol-demethylation inhibitor (DMI) in S. homoeocarpa populations have been widely reported in the United States. Moreover, the occurrence of S. homoeocarpa populations with multiple fungicide resistance (MFR) is a growing problem on golf courses. The present study was undertaken to evaluate the efficacy of DMI, dicarboximide, and SDHI against a S. homoeocarpa population with MFR on a Connecticut golf course fairway from 2014 to 2016. Also, because the S. homoeocarpa population consisted of four different phenotypes with differing resistance profiles to benzimidazole, dicarboximide, and DMI, in vitro sensitivity assays were used to understand the dynamics of the MFR population in the presence and absence of fungicide selection pressures. Results indicated that boscalid fungicide (SDHI) was able to provide an acceptable control of the MFR dollar spot population. Propiconazole or iprodione application selected isolates with both DMI and dicarboximide resistance (DMI-R/Dicar-R). In the absence of fungicide selection pressures, the percent frequency of DMI-R/Dicar-R or DMI and benzimidazole resistance (DMI-R/Ben-R) isolates declined in the population. Out of the four phenotypes, the percent frequency of isolates with DMI, dicarboximide, and benzimidazole resistance (DMI-R/Dicar-R/Ben-R) was the lowest in the population regardless of fungicide selection pressures. Our first report of MFR population dynamics will help develop effective strategies for managing MFR and potentially delay the emergence of future resistant populations in S. homoeocarpa.
Nematicides, Starter Fertilizers, and Plant Growth Regulators Implementation into a Corn Production System
Authors: Till Stephen , Lawrence Kathy , Donald Patricia , Schrimsher Drew
Published: September 2018

The southern root-knot nematode, Meloidogyne incognita, is one of the most important nematode pathogens in Alabama owing to its wide host range and yield loss on major agronomic crops. Management of root-knot nematode is undervalued in corn production owing to relatively low prices for corn at the market, less obvious symptoms, and smaller yield losses compared with cotton and soybeans, plus an overall lack of management options. However, growing successive susceptible crops in root-knot nematode-infested fields only heightens the risk of future yield loss. We evaluated use of starter fertilizers and plant growth regulators with nematicides as an economically viable option to reduce the impact of M. incognita on corn. In 2 years of research, we concluded that the combination of all three inputs provided positive economic returns in only one out of four trials. In 2016, the location with the lower root-knot nematode population density saw significant advantages with these input combinations. In 2017, dramatic advantages in early plant growth were observed with a variety of combinations, but owing to unfavorable growing conditions, yield increases were not observed. We concluded that an early plant growth increase due to applications of starter fertilizers, plant growth regulators, and nematicides often did not correlate to increased yield, although the potential exists.
Hazelnut Yield Protection Using Fungicides Against Eastern Filbert Blight
Authors: Pscheidt Jay W. , Bassinette John P. , Heckert Stephanie , Cluskey Steve A.
Published: September 2018

Fungicide effectiveness on yield loss owing to eastern filbert blight (EFB) was studied on mature, bearing hazelnut trees in a replicated trial. This case study found that fungicide use in hazelnuts not only limited EFB development but also protected future yield loss and gross financial returns. The results were similar to commercial industry experience even though the research occurred on small blocks of mature trees. There was no difference in disease or yield between the two fungicide programs evaluated. Growers who carry the annual cost of fungicides after discovery of EFB in their orchards will benefit monetarily several years later through sustained yields.
Cautionary Notes on Use of the MoT3 Diagnostic Assay for Magnaporthe oryzae Wheat and Rice Blast Isolates
Authors: Gupta Dipali Rani , Avila Claudia Sarai Reyes , Win Joe , Soanes Darren M. , Ryder Lauren S. , Croll Daniel , Bhattacharjee Pallab , Hossain Md. Shaid , Mahmud Nur Uddin , Mehebub Md. Shabab , Surovy Musrat Zahan , Rahman Md. Mahbubur , Talbot Nicholas J. , Kamoun Sophien , Islam M. Tofazzal
Published: September 2018

The blast fungus Magnaporthe oryzae is comprised of lineages that exhibit varying degrees of specificity on about 50 grass hosts, including rice, wheat, and barley. Reliable diagnostic tools are essential given that the pathogen has a propensity to jump to new hosts and spread to new geographic regions. Of particular concern is wheat blast, which has suddenly appeared in Bangladesh in 2016 before spreading to neighboring India. In these Asian countries, wheat blast strains are now co-occurring with the destructive rice blast pathogen raising the possibility of genetic exchange between these destructive pathogens. We assessed the recently described MoT3 diagnostic assay and found that it did not distinguish between wheat and rice blast isolates from Bangladesh. The assay is based on primers matching the WB12 sequence corresponding to a fragment of the M. oryzae MGG_02337 gene annotated as a short chain dehydrogenase. These primers could not reliably distinguish between wheat and rice blast isolates from Bangladesh based on DNA amplification experiments performed in separate laboratories in Bangladesh and in the United Kingdom. Specifically, all eight rice blast isolates tested in this study produced the WB12 amplicon. In addition, comparative genomics of the WB12 nucleotide sequence revealed a complex underlying genetic structure with related sequences across M. oryzae strains and in both rice and wheat blast isolates. We, therefore, caution against the indiscriminate use of this assay to identify wheat blast and encourage further development of the assay to ensure its value in diagnosis.
Plant Defensin Peptides have Antifungal and Antibacterial Activity Against Human and Plant Pathogens
Authors: Sathoff Andrew E. , Velivelli Siva , Shah Dilip M. , Samac Deborah A.
Published: September 2018

Plant defensins are small, cysteine-rich antimicrobial peptides. These peptides have previously been shown to primarily inhibit the growth of fungal plant pathogens. Plant defensins have a γ-core motif, defined as GXCX3-9C, which is required for their antifungal activity. To evaluate plant defensins as a potential control for a problematic agricultural disease (alfalfa crown rot), short, chemically synthesized peptides containing γ-core motif sequences were screened for activity against numerous crown rot pathogens. These peptides showed both antifungal and, surprisingly, antibacterial activity. Core motif peptides from Medicago truncatula defensins (MtDef4 and MtDef5) displayed high activity against both plant and human bacterial pathogens in vitro. Full-length defensins had higher antimicrobial activity compared with the peptides containing their predictive γ-core motifs. These results show the future promise for controlling a wide array of economically important fungal and bacterial plant pathogens through the transgenic expression of a plant defensin. They also suggest that plant defensins may be an untapped reservoir for development of therapeutic compounds for combating human and animal pathogens.
Genetic diversity of hepatitis B virus in Yunnan, China: identification of novel subgenotype C17, an intergenotypic B/I recombinant, and B/C recombinants
Authors: Feng Yue , Ran Jieyu , Feng Yue-Mei , Miao Jing , Zhao Yue , Jia Yuanyuan , Li Zheng , Yue Wei , Xia Xueshan
Published: September 2018

Yunnan is considered to be a geographical hotspot for the introduction, mutation and recombination of several viruses in China. However, there are limited data regarding the genotypic profiles of hepatitis B virus (HBV) in this region. In this study, we characterized 206 HBV strains isolated from chronic hepatitis B patients in Yunnan, China. Initial genotyping based on 1.5 kb sequences revealed that genotype C was the most prevalent at 52.4 % (108/206), followed by genotype B at 30.6 % (63/206) and unclassified genotypes at 17.0 % (35/206). To characterize the 35 unclassified strains, 32 complete HBV genomes were amplified and analysed; 17 isolates were classified within a known subgenotype, 8 were classified as B/C recombinants, 1 was classified as a B/I recombinant and 6 constituted a potentially novel C subgenotype that we designated as C17, based on the characteristics of a monophyletic cluster, >4 % genetic distances, no significant evidence of recombination and no epidemiological link among individuals. Thus, multiple subgenotypes – namely B1, B2, B4, C1, C2, C3, C4, C8 and C17 – and two distinct intergenotypic recombinants exist in Yunnan, China, highlighting the complex and diverse distribution pattern of HBV genotypic profiles.
A comprehensive data-driven model of cat primary visual cortex
Authors: Antolík Ján , Cagnol Rémy , Rózsa Tibor , Monier Cyril , Frégnac Yves , Davison Andrew P.
Published: September 2018

1

Knowledge integration based on the relationship between structure and function of the neural substrate is one of the main targets of neuroinformatics and data-driven computational modeling. However, the multiplicity of data sources, the diversity of benchmarks, the mixing of observables of different natures, and the necessity of a long-term, systematic approach make such a task challenging. Here we present a first snapshot of a long-term integrative modeling program designed to address this issue in the domain of the visual system: a comprehensive spiking model of cat primary visual cortex. The presented model satisfies an extensive range of anatomical, statistical and functional constraints under a wide range of visual input statistics. In the presence of physiological levels of tonic stochastic bombardment by spontaneous thalamic activity, the modelled cortical reverberations self-generate a sparse asynchronous ongoing activity that quantitatively matches a range of experimentally measured statistics. When integrating feed-forward drive elicited by a high diversity of visual contexts, the simulated network produces a realistic, quantitatively accurate interplay between visually evoked excitatory and inhibitory conductances; contrast-invariant orientation-tuning width; center surround interactions; and stimulus-dependent changes in the precision of the neural code. This integrative model offers insights into how the studied properties interact, contributing to a better understanding of visual cortical dynamics. It provides a basis for future development towards a comprehensive model of low-level perception.

2

Author summary

Computational modeling can integrate fragments of understanding generated by experimental neuroscience. However, most models considered only a few features of neural computation at a time, leading to either poorly constrained models with many parameters, or lack of expressiveness in over-simplified models. A solution is to develop detailed models, but constrain them with a broad range of anatomical and functional data to prevent overfitting. This requires a long-term systematic approach. Here we present a first snapshot of such an integrative program: a large-scale spiking model of cat primary visual cortex, that is constrained by an extensive range of anatomical and functional features. Together with the associated modeling infrastructure, this study lays the groundwork for a broad integrative modeling program seeking an in-depth understanding of vision.
Evidence for metacognitive bias in perception of voluntary action
Authors: Charles Lucie , Chardin Camille , Haggard Patrick
Published: September 2018

Studies of metacognition often measure confidence in perceptual decisions. Much less is known about metacognition of action, and specifically about how people estimate the success of their own actions. In the present study, we compare metacognitive abilities between voluntary actions, passive movements matched to those actions, and purely visual signals. Participants reported their confidence in judging whether a brief visual probe appeared ahead or behind of their finger during simple flexion/extension movement. The finger could be moved voluntarily, or could be moved passively by a robot replaying their own previous movements. In a third condition, participants did not move, but a visual cursor replayed their previous voluntary movements. Metacognitive sensitivity was comparable when judging active movements, during passive finger displacement and visual cursor reply. However, a progressive metacognitive bias towards overconfidence was found for passive and for voluntary movements. Taken together, our results may partly explain some of the peculiarities that arise when one judges one’s own actions.
Exosome Release Promotes Inflammatory Resolution in Activated and Aged Microglia
Authors: Udeochu Joe C. , Sanchez-Diaz Cesar , Cai Alvan , Jovicic Anna , Villeda Saul A.
Published: September 2018

Proper regulation of inflammatory responses is critical for effective function of microglia, in both physiological and disease states. While the mechanisms that drive microglia activation are well characterized, the pathways leading to inflammatory resolution and immune homeostasis have yet to be fully elucidated. Using RNA interference, pharmacological inhibition and genetic knockout mouse model approaches, we show that exosome release promotes immune homeostasis in activated and aged microglia. We demonstrate that induction of anti-inflammatory pathways enhances release of exosomes containing immune proteins and microRNAs. Functionally, inhibition of exosome release alters trafficking of exosome cargo, such as miR-155, in activated microglia resulting in increased cellular retention of these cargo molecules. Concordantly, we identify increased miR-155 activity leading to sustained activation of pro-inflammatory pathways as a potential mechanism underlying impaired inflammatory resolution due to inhibition of microglia exosome release. Similarly, inhibition of augmented exosome release in aged microglia exacerbates inflammatory activation, demonstrating conservation of the immune modulatory effects of exosome release in microglia. Taken together, our study identifies exosomes as novel components of an anti-inflammatory mechanism utilized by activated and aged microglia to restore immune homeostasis.
Optimisation and validation of hydrogel-based brain tissue clearing shows uniform expansion across anatomical regions and spatial scales
Authors: Tyson Adam L. , Akhtar Ayesha , Andreae Laura C.
Published: September 2018

Imaging of fixed tissue is routine in experimental neuroscience, but is limited by the depth of tissue that can be imaged using conventional methods. Optical clearing of brain tissue using hydrogel-based methods (e.g. CLARITY) allows imaging of large volumes of tissue and is rapidly becoming commonplace in the field. However, these methods suffer from a lack of standardised protocols and validation of the effect they have upon tissue morphology. We present a simple and reliable protocol for tissue clearing along with a quantitative assessment of the effect of tissue clearing upon morphology. Tissue clearing caused tissue swelling (compared to conventional methods), but this swelling was shown to be similar across spatial scales and the variation was within limits acceptable to the field. The results of many studies rely upon an assumption of uniformity in tissue swelling, and by demonstrating this quantitatively, research using these methods can be interpreted more reliably.
Tunneling nanotubes contribute to the stroma-mediated imatinib resistance of leukemic cells
Authors: Kolba Marta D. , Dudka Wioleta , Zaręba-Kozioł Monika , Kominek Agata , Ronchi Paolo , Turos Laura , Wlodarczyk Jakub , Schwab Yannick , Cysewski Dominik , Srpan Katja , Davis Daniel M. , Piwocka Katarzyna
Published: September 2018

Intercellular communication within the bone marrow niche significantly influences leukemogenesis and the sensitivity of leukemic cells to therapy. Tunneling nanotubes (TNTs) are a novel mode of intercellular cross-talk. They are long, thin membranous protrusions that enable the direct transfer of various cargo between cells. Here we show that TNTs are formed between leukemic and bone marrow stromal cells. Fluorescence confocal microscopy with 3D reconstructions, correlative light-electron microscopy and electron tomography provided evidence that TNTs transfer cellular vesicles between cells. The quantitative analysis demonstrated that the stromal cells stimulate TNT-mediated vesicle transfer towards leukemic cells. Transfer of vesicular cargo from stromal cells correlated with increased resistance to anti-leukemic treatment. Moreover, specific sets of proteins with a potential role in survival and the drug response were transferred within these vesicles. Altogether, we found that TNTs are involved in the leukemia-stroma cross-talk and the stroma-mediated cytoprotection of leukemic cells. Our findings implicate TNT connections as a possible target for therapeutic interventions within the leukemia microenvironment to attenuate stroma-conferred protection.
Trans effects on gene expression can drive omnigenic inheritance
Authors: Liu Xuanyao , Li Yang I , Pritchard Jonathan K
Published: September 2018

Early genome-wide association studies (GWAS) led to the surprising discovery that, for typical complex traits, the most significant genetic variants contribute only a small fraction of the estimated heritability. Instead, it has become clear that a huge number of common variants, each with tiny effects, explain most of the heritability. Previously, we argued that these patterns conﬂict with standard conceptual models, and that new models are needed. Here we provide a formal model in which genetic contributions to complex traits can be partitioned into direct effects from core genes, and indirect effects from peripheral genes acting as trans-regulators. We argue that the central importance of peripheral genes is a direct consequence of the large contribution of trans-acting variation to gene expression variation. In particular, we propose that if the core genes for a trait are co-regulated – as seems likely – then the effects of peripheral variation can be amplified by these co-regulated networks such that nearly all of the genetic variance is driven by peripheral genes. Thus our model proposes a framework for understanding key features of the architecture of complex traits.
Generation of human neural retina transcriptome atlas by single cell RNA sequencing
Authors: Lukowski Samuel W. , Lo Camden Y. , Sharov Alexei , Nguyen Quan H. , Fang Lyujie , Hung Sandy S.C. , Zhu Ling , Zhang Ting , Nguyen Tu , Senabouth Anne , Jabbari Jafar S. , Welby Emily , Sowden Jane C. , Waugh Hayley S. , Mackey Adrienne , Pollock Graeme , Lamb Trevor D. , Wang Peng-Yuan , Hewitt Alex W. , Gillies Mark , Powell Joseph E. , Wong Raymond C.B.
Published: September 2018

The retina is a highly specialized neural tissue that senses light and initiates image processing. Although the functional organisation of specific cells within the retina has been well-studied, the molecular profile of many cell types remains unclear in humans. To comprehensively profile cell types in the human retina, we performed single cell RNA-sequencing on 20,009 cells obtained post-mortem from three donors and compiled a reference transcriptome atlas. Using unsupervised clustering analysis, we identified 18 transcriptionally distinct clusters representing all known retinal cells: rod photoreceptors, cone photoreceptors, Müller glia cells, bipolar cells, amacrine cells, retinal ganglion cells, horizontal cells, retinal astrocytes and microglia. Notably, our data captured molecular profiles for healthy and early degenerating rod photoreceptors, and revealed a novel role of MALAT1 in putative rod degeneration. We also demonstrated the use of this retina transcriptome atlas to benchmark pluripotent stem cell-derived cone photoreceptors and an adult Müller glia cell line. This work provides an important reference with unprecedented insights into the transcriptional landscape of human retinal cells, which is fundamental to our understanding of retinal biology and disease.
Id4 eliminates the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells
Authors: Blomfield Isabelle , Rocamonde Brenda , del Mar Masdeu Maria , Mulugeta Eskeatnaf , Vaga Stefania , van den Berg Debbie L. C. , Huillard Emmanuelle , Guillemot François , Urbán Noelia
Published: September 2018

Quiescence is essential for the long-term maintenance of adult stem cells and tissue homeostasis. However, how stem cells maintain quiescence is still poorly understood. Here we show that stem cells in the dentate gyrus of the adult hippocampus actively transcribe the pro-activation factor Ascl1 regardless of their activation state. We found that the inhibitor of DNA binding protein Id4 suppresses Ascl1 activity in neural stem cell cultures. Id4 sequesters Ascl1 heterodimerisation partner E47, promoting Ascl1 protein degradation and neural stem cell quiescence. Accordingly, elimination of Id4 from stem cells in the adult hippocampus results in abnormal accumulation of Ascl1 protein and premature stem cell activation. We also found that multiple signalling pathways converge on the regulation of Id4 to reduce the activity of hippocampal stem cells. Id4 therefore maintains quiescence of adult neural stem cells, in sharp contrast with its role of promoting the proliferation of embryonic neural progenitors.
An Alternative Framework for Fluorescence Correlation Spectroscopy
Authors: Jazani Sina , Sgouralis Ioannis , Shafraz Omer M. , Levitus Marcia , Sivasankar Sanjeevi , Pressé Steve
Published: September 2018

Fluorescence correlation spectroscopy (FCS), is a flexible and widely used tool routinely exploited forin vivoandin vitroapplications. While FCS provides estimates of dynamical quantities, such as diffusion coefficients, it demands high signal to noise ratios and long time traces, typically in the minute range. In principle, the same information can be extracted fromµ-s long time traces; however, an appropriate analysis method is missing. To overcome these limitations, we adapt novel tools inspired by Bayesian non-parametrics, which starts from the direct analysis of the observed photon counts. With this approach, we are able to analyze time traces, which are too short to be analyzed by existing methods, including FCS. Our new analysis extends the capability of single molecule fluorescence confocal microscopy based approaches, to probe processes several orders of magnitude faster in time and permits a reduction of phototoxic effects on living samples induced by long periods of light exposure.
The second edge of ADHD: an advantage in motor learning and performance with task-irrelevant background vibratory noise
Authors: Korman Maria , Meir-Yalon Lian , Egbarieh Nebal , Karni Avi
Published: September 2018

Young adults with ADHD often gain less than expected from practice sessions well-suited for their peers. Here, we tested whether task-irrelevant, low-intensity vibratory stimulation (VtSt), suggested to modulate motor learning, may compensate for such learning deficits. Participants were given training, either with or without VtSt, on a sequence of finger opposition movements. Under VtSt, typical individuals had reduced overnight, consolidation phase, gains; performance partly recovering one week later. In contrast, participants with ADHD benefitted from VtSt both during the acquisition (online) and the overnight skill consolidation (offline) phases. One week later, both groups showed robust retention of the gains in performance, but when tested with background VtSt, individuals with ADHD outperformed their typical peers. We propose that ADHD can confer advantages in performance, learning and skill memory consolidation in specific ‘noisy’ conditions that adversely affect typical adults; we conjecture that the effects of VtSt are contingent on baseline arousal levels.
beditor: A computational workflow for designing libraries of guide RNAs for CRISPR-mediated base editing
Authors: Dandage Rohan , Després Philippe C , Yachie Nozomu , Landry Christian R
Published: September 2018

CRISPR-mediated base editors have opened unique avenues for scar-free genome-wide mutagenesis. Here, we describe a comprehensive computational workflow called beditor that can be broadly adapted for designing guide RNA libraries with a range of CRISPR-mediated base editors, PAM recognition sequences and genomes of many species. Additionally, in order to assist users in selecting the best sets of guide RNAs for their experiments, a priori estimates, called beditor scores are calculated. These beditor scores are intended to select guide RNAs that conform to requirements for optimal base editing: the editable base falls within maximum activity window of the CRISPR-mediated base editor and produces non-confounding mutational effects with minimal predicted off-target effects. We demonstrate the utility of the software by designing guide RNAs for base-editing to create or remove thousands of clinically important human disease mutations.
Infection-generated electric field in gut epithelium drives bidirectional migration of macrophages
Authors: Sun Yaohui , Reid Brian , Ferreira Fernando , Luxardi Guillaume , Ma Li , Lokken Kristen L. , Zhu Kan , Xu Gege , Sun Yuxin , Ryzhuk Volodymyr , Guo Betty P. , Lebrilla Carlito B. , Maverakis Emanual M. , Mogilner Alex , Zhao Min
Published: September 2018

Many bacterial pathogens hijack macrophages to egress from the port of entry to the lymphatic/blood-stream, causing dissemination of life-threatening infections. However, the underlying mechanisms are not well understood. Here, we report thatSalmonellainfection generates directional electric fields (EF) in the follicle-associated epithelium of mouse cecum.In vitroapplication of an EF, mimicking the infection-generated electric field (IGEF), induces directional migration of primary mouse macrophages to the anode, which is reversed to the cathode uponSalmonellainfection. This infection-dependent directional switch is independent of theSalmonellapathogenicity island 1 (SPI-1) type III secretion system. The switch is accompanied by a reduction of sialic acids on glycosylated surface components during phagocytosis of bacteria, which is absent in macrophages challenged by microspheres. Moreover, enzymatic cleavage of terminally exposed sialic acids reduces macrophage surface negativity and severely impairs directional migration of macrophages in response to EF. Based on these findings, we propose that macrophages are attracted to the site of infection by a combination of chemotaxis and galvanotaxis; after phagocytosis of bacteria, surface electrical properties of the macrophage change, and galvanotaxis directs the cells away from the site of infection.

Abbreviations

CFU, colony-forming unit; Con A, Concanavalin A; EF, electric field; FAE, follicle-associated epithelium; GNL, Galanthus Nivalis lectin; IGEF, infection-generated electric field; Ji, electric current density; MAL-2, Maackia Amurensis lectin II; MLN, mesenteric lymph node; MOI, multiplicity of infection; nMFI, normalized mean fluorescence intensity; RCA-1, Ricinus Communis Agglutinin I; SNA, Sambucus Nigra lectin;S. Typhimurium,Salmonella entericaserotype Typhimurium; SPI-1,Salmonellapathogenicity island 1; PDMS, polydimethylsiloxane; TEP, trans-epithelial potential difference; TLR, Toll-like receptors; WGEF, wound-generated electric field
Arabidopsis RUP2 represses UVR8-mediated flowering in noninductive photoperiods
Authors: Arongaus Adriana B. , Chen Song , Pireyre Marie , Glöckner Nina , Galvão Vinicius C. , Albert Andreas , Winkler J. Barbro , Fankhauser Christian , Harter Klaus , Ulm Roman
Published: September 2018

Plants have evolved complex photoreceptor-controlled mechanisms to sense and respond to seasonal changes in day length. This ability allows plants to optimally time the transition from vegetative growth to flowering. UV-B is an important part intrinsic to sunlight; however, whether and how it affects photoperiodic flowering has remained elusive. Here, we report that, in the presence of UV-B, genetic mutation of REPRESSOR OF UV-B PHOTOMORPHOGENESIS 2 (RUP2) renders the facultative long day plant Arabidopsis thaliana a day-neutral plant and that this phenotype is dependent on the UV RESISTANCE LOCUS 8 (UVR8) UV-B photoreceptor. We provide evidence that the floral repression activity of RUP2 involves direct interaction with CONSTANS, repression of this key activator of flowering, and suppression of FLOWERING LOCUS T transcription. RUP2 therefore functions as an essential repressor of UVR8-mediated induction of flowering under noninductive short day conditions and thus provides a crucial mechanism of photoperiodic flowering control.
High-throughput characterization of genetic effects on DNA–protein binding and gene transcription
Authors: Kalita Cynthia A. , Brown Christopher D. , Freiman Andrew , Isherwood Jenna , Wen Xiaoquan , Pique-Regi Roger , Luca Francesca
Published: September 2018

Many variants associated with complex traits are in noncoding regions and contribute to phenotypes by disrupting regulatory sequences. To characterize these variants, we developed a streamlined protocol for a high-throughput reporter assay, Biallelic Targeted STARR-seq (BiT-STARR-seq), that identifies allele-specific expression (ASE) while accounting for PCR duplicates through unique molecular identifiers. We tested 75,501 oligos (43,500 SNPs) and identified 2720 SNPs with significant ASE (FDR < 10%). To validate disruption of binding as one of the mechanisms underlying ASE, we developed a new high-throughput allele-specific binding assay for NFKB1. We identified 2684 SNPs with allele-specific binding (ASB) (FDR < 10%); 256 of these SNPs also had ASE (OR = 1.97,P-value = 0.0006). Of variants associated with complex traits, 1531 resulted in ASE, and 1662 showed ASB. For example, we characterized that the Crohn's disease risk variant for rs3810936 increases NFKB1 binding and results in altered gene expression.
Crystal structures of the solvent-free and ethanol disolvate forms of 4,4′-(diazenediyl)bis(2,3,5,6-tetrafluorobenzoic acid) exemplifying self-stabilized azobenzene cis-configurations
Authors: Elkin Igor , Maris Thierry , Hildgen Patrice , Barrett Christopher J.
Published: September 2018

cis-4,4′-(Diazenediyl)bis(2,3,5,6-tetrafluorobenzoic acid), C14H2F8N2O4, and its ethanol disolvate, C14H2F8N2O4·2C2H5OH, represent new examples of self-stabilized cis-configured azobenzenes obtained by a common crystallization procedure at room temperature under normal laboratory lighting conditions. The target structure constitutes of two 2,3,5,6-tetrafluorobenzoic acid residues linked to each other by a cis-configured azo group and was confirmed for two isolated specimens extracted from the same sample, corresponding to a solvent-free form and an ethanol disolvate. In the solvent-free form, the molecule is characterized by rotational symmetry around a twofold rotation axis bisecting its central N=N bond while this symmetry is not present in the solvated form. The values of the inclination angles of the terminal carboxyl groups towards the corresponding benzene rings vary from 5.2 (4) to 45.7 (2)°, depending on the crystal composition. In the unsolvated form, the molecules are linked through identical hydrogen bonds with a classical R
2
2(8) graph-set ring motif of carboxylic acids, by generating supramolecular chains running approximately parallel to [101]. The presence of ethanol in the solvated form also leads to changes in the short-contact pattern to produce both the R
4
4(12) ring and open-chain motifs with alternating alcohol and dicarboxylic acid molecules.
Different classical hydrogen-bonding patterns in three salicylaldoxime derivatives, 2-HO-4-XC6H3C=NOH (X= Me, OH and MeO)
Authors: Gomes Ligia R. , Souza Marcus V. N. de , Da Costa Cristiane F. , Wardell James L. , Low John Nicolson
Published: September 2018

The crystal structures of three salicyaldoxime compounds, namely 2-hydroxy-4-methylbenzaldehyde oxime, C8H9NO2,1, 2,4-dihydroxybenzaldehyde oxime, C7H7NO3,2, and 2-hydroxy-4-methoxybenzaldehyde oxime, C8H9NO3,3, are discussed. In each compound, the hydroxyl groups are essentially coplanar with their attached phenyl group. The interplanar angles between the C=N—O moieties of the oxime unit and their attached phenyl rings are 0.08 (9), 1.08 (15) and 6.65 (15)° in1,2and3, respectively. In all three molecules, the 2-hydroxy group forms an intramolecular O—H...N(oxime) hydrogen bond. In compound (1), intermolecular O—H(oxime)...O(hydroxyl) hydrogen bonds generateR22(14) dimers, related by inversion centres. In compound2, intermolecular O—H(oxime)...O(4-hydroxy) hydrogen bonds generateC9 chains along theb-axis direction, while O—H(4-hydroxyl)...O(2-hydroxyl) interactions form zigzagC6 spiral chains along the c-axis direction, generated by a screw axis at 1,y, 1/4: the combination of the two chains provides a bimolecular sheet running parallel to thebaxis, which lies between 0–1/2cand 1/2–1c. In compound3, similarC9 chains, along theb-axis direction are generated by O—H(oxime)...O(4-methoxy) hydrogen bonds. Further weaker, C—H...π (in1), π–π (in2) and both C—H...π and π–π interactions (in3) further cement the three-dimensional structures. Hirshfeld surface and fingerprint analyses are discussed.
L-Histidinium iodide
Authors: Catherine P. , Kumar P. Praveen , Gunasekaran B.
Published: September 2018

In the title salt, C6H10N3O2
+·I−, the cation is protonated at the imidazole ring and the amine group and deprotonated at the carboxylate group. The crystal packing features N—H...O and N—H...I hydrogen bonds.