bluuebunny/crossref_metadata_2025 huggingface dataset:
Capsidiol, a defensive sesquiterpene produced by wild tobacco in response to attack from the fungal pathogenAlternaria alternata, is regulated by an ERF2-like transcription factor
Authors: Song Na , Ma Lan , Wang Weiguang , Sun Huanhuan , Wang Lei , Baldwin Ian T. , Wu Jinsong
Published: March 2019

Capsidiol is a sesquiterpenoid phytoalexin produced inNicotianaandCapsicumspecies in response to pathogen attack. Whether capsidiol plays a defensive role and how its biosynthesis is regulated in the wild tobaccoNicotiana attenuatawhen the plant is attacked byAlternaria alternata(tobacco pathotype), a notorious necrotrophic fungus causing brown spot disease, is unknown. Transcriptome analysis indicated that a metabolic switch to sesquiterpene biosynthesis occurred in young leaves ofN. attenuataafterA. alternatainoculation: many genes leading to sesquiterpene production were strongly up-regulated, including the capsidiol biosynthetic genes, 5-epi-aristolochene synthase(EAS) and 5-epi-aristolochene hydroxylase(EAH). Consistently, the level of capsidiol was increased dramatically in young leaves after fungal inoculation, from not detectable in mock control to 50.68 ± 3.10 µg/g fresh leaves at 3 days post inoculation. Capsidiol-reduced or capsidiol-depleted plants, which were generated by silencingEAHs orEASs by virus-induced gene silencing, were more susceptible to the fungus. In addition, this sesquiterpene exhibited strong anti-fungal activities againstA. alternata in vitrowhen purified from infected plants and applied to fungal growth. Furthermore, an ERF2-like transcription factor was found to positively regulate capsidiol production and plant resistance through the direct transactivation of a capsidiol biosynthetic geneEAS12. Taken together, our results demonstrate that capsidiol, a phytoalexin highly accumulated inN. attenuataplants in response toA. alternatainfection, plays an important role in pathogen resistance independent of JA and ethylene signaling pathways, and its biosynthesis is transcriptionally regulated by an ERF2-like transcription factor.

Highlight

Our results demonstrate that capsidiol, a phytoalexin highly accumulated inNicotiana attenuataplants in response toAlternaria alternataattack, plays an important role in pathogen resistance, and its biosynthesis is transcriptionally regulated by an ERF2-like transcription factor.
Sequential compression of gene expression across dimensionalities and methods reveals no single best method or dimensionality
Authors: Way Gregory P. , Zietz Michael , Rubinetti Vincent , Himmelstein Daniel S. , Greene Casey S.
Published: March 2019

Background

Unsupervised compression algorithms applied to gene expression data extract latent, or hidden, signals representing technical and biological sources of variation. However, these algorithms require a user to select a biologically-appropriate latent dimensionality. In practice, most researchers select a single algorithm and latent dimensionality. We sought to determine the extent by which using multiple dimensionalities across ensemble compression models improves biological representations.

Results

We compressed gene expression data from three large datasets consisting of adult normal tissue, adult cancer tissue, and pediatric cancer tissue. We compressed these data into many latent dimensionalities ranging from 2 to 200. We observed various tradeoffs across latent dimensionalities and compression models. For example, we observed high model stability between principal components analysis (PCA), independent components analysis (ICA), and non-negative matrix factorization (NMF). We identified more unique biological signatures in ensembles of denoising autoencoder (DAE) and variational autoencoder (VAE) models in intermediate latent dimensionalities. However, we captured the most pathway-associated features using all compressed features across algorithms and dimensionalities. Optimized at different latent dimensionalities, compression models detect generalizable gene expression signatures representing sex, neuroblastoma MYCN amplification, and cell types. In two supervised machine learning tasks, compressed features optimized predictions at different latent dimensionalities.

Conclusions

There is no single best latent dimensionality or compression algorithm for analyzing gene expression data. Instead, using feature ensembles from different compression models across latent space dimensionalities optimizes biological representations.
Conserved residues in the wheat (Triticum aestivum) NAM-A1 NAC domain are required for protein binding and when mutated lead to delayed peduncle and flag leaf senescence
Authors: Harrington Sophie A. , Overend Lauren E. , Cobo Nicolas , Borrill Philippa , Uauy Cristobal
Published: March 2019

Background

NAC transcription factors contain five highly conserved subdomains which are required for protein dimerisation and DNA binding. Few residues within these subdomains have been identified as essential for protein function, and fewer still have been shown to be of biological relevancein planta. Here we use a positive regulator of senescence in wheat,NAM-A1, to test the impact of missense mutations at specific, highly conserved residues of the NAC domain on protein function.

Results

We identified missense mutations in five highly conserved residues of the NAC domain ofNAM-A1in a tetraploid TILLING population. TILLING lines containing these mutations, alongside synonymous and non-conserved mutation controls, were grown under glasshouse conditions and scored for senescence. Four of the five mutations showed a significant and consistent delay in peduncle senescence but had no consistent effects on flag leaf senescence. All four mutant alleles with the delayed senescence phenotype also lost the ability to interact with the homoeolog NAM-B1 in a yeast two-hybrid assay. Two of these residues were previously shown to be involved in NAC domain function in Arabidopsis, suggesting conservation of residue function between species. Three of these four alleles led to an attenuated cell death response compared to wild-typeNAM-A1when transiently over-expressed inNicotiana benthamiana. One of these mutations was further tested under field conditions, in which there was a significant and consistent delay in both peduncle and leaf senescence.

Conclusions

We combined field and glasshouse studies of a series of mutant alleles with biochemical analyses to identify four residues of the NAC domain which are required forNAM-A1function and protein interaction. We show that mutations in these residues lead to a gradient of phenotypes, raising the possibility of developing allelic series of mutations for traits of agronomic importance. We also show that mutations inNAM-A1more severely impact peduncle senescence, compared to the more commonly studied flag leaf senescence, highlighting this as an area deserving of further study. The results from this integrated approach provide strong evidence that conserved residues within the functional domains of NAC transcription factors have biological significancein planta.
Structure elucidation of colibactin
Authors: Xue Mengzhao , Kim Chung Sub , Healy Alan R. , Wernke Kevin M. , Wang Zhixun , Frischling Madeline C. , Shine Emilee E. , Wang Weiwei , Herzon Seth B. , Crawford Jason M.
Published: March 2019

Colibactin is a gut microbiome metabolite of unknown structure that has been implicated in colorectal cancer formation. Several studies now suggest that the tumorgenicity of colibactin derives from interstrand cross-linking of host DNA. Here we use a combination of genetics, isotope labeling, tandem MS, and chemical synthesis to deduce the structure of colibactin. Our structural assignment accounts for all known biosynthetic data and suggests roles for the final unaccounted enzymes in the colibactin gene cluster. DNA cross-link degradation products derived from synthetic and natural colibactin were indistinguishable by tandem MS analysis, thereby confirming the structure prediction. This work reveals the structure of colibactin, which has remained incompletely defined for over a decade.
Propagation of cortical activity via open-loop intrathalamic architectures: a computational analysis
Authors: Brown Jeffrey W. , Taheri Aynaz , Kenyon Robert V. , Berger-Wolf Tanya , Llano Daniel A.
Published: March 2019

Propagation of signals across the cerebral cortex is a core component of many cognitive processes and is generally thought to be mediated by direct intracortical connectivity. The thalamus, by contrast, is considered to be devoid of internal connections and organized as a collection of parallel inputs to the cortex. Here, we provide evidence that “open-loop” intrathalamic connections involving the thalamic reticular nucleus (TRN) can support propagation of oscillatory activity across the cortex. Recent studies support the existence of open-loop thalamo-reticulo-thalamic (TC-TRN-TC) synaptic motifs in addition to traditional closed-loop architectures. We hypothesized that open-loop structural modules, when connected in series, might underlie thalamic and, therefore cortical, signal propagation. Using a supercomputing platform to simulate thousands of permutations of a thalamo-reticular-cortical network and allowing select synapses to vary both by class and individually, we evaluated the relative capacities of closed- and open-loop TC-TRN-TC synaptic configurations to support both propagation and oscillation. We observed that 1) signal propagation was best supported in networks possessing strong open-loop TC-TRN-TC connectivity; 2) intrareticular synapses were neither primary substrates of propagation nor oscillation; and 3) heterogeneous synaptic networks supported more robust propagation of oscillation than their homogeneous counterparts. These findings suggest that open-loop heterogeneous intrathalamic architectures complement direct intracortical connectivity to facilitate cortical signal propagation.

Significance Statement

Interactions between the dorsal thalamus and thalamic reticular nucleus (TRN) are speculated to contribute to phenomena such as arousal, attention, sleep, and seizures. Despite the importance of the TRN, the synaptic microarchitectures forming the basis for dorsal thalamus-TRN interactions are not fully understood. The computational neural model we present incorporates “open-loop” thalamo-reticular-thalamic (TC-TRN-TC) synaptic motifs, which have been experimentally observed. We elucidate how open-loop motifs possess the capacity to shape the propagative properties of signals intrinsic to the thalamus and evaluate the wave dynamics they support relative to closed-loop TC-TRN-TC pathways and intrareticular synaptic connections. Our model also generates predictions regarding how different spatial distributions of reticulothalamic and intrareticular synapses affect these signaling properties.
A pivotal genetic program controlled by thyroid hormone during the maturation of GABAergic neurons in mice
Authors: Richard Sabine , Guyot Romain , Rey-Millet Martin , Prieux Margaux , Markossian Suzy , Aubert Denise , Flamant Frédéric
Published: March 2019

In mammals, brain development is critically dependent on proper thyroid hormone signaling, via the TRα1 nuclear receptor. However, the downstream mechanisms by which TRα1 impacts brain development are currently unknown, notably because this receptor is expressed ubiquitously from early stages of development. In order to better define the function of TRα1 in the developing brain, we used mouse genetics to induce the expression of a dominant-negative mutation of the receptor specifically in GABAergic neurons, the main inhibitory neurons in the brain, which were previously identified as sensitive to hypothyroidism. This triggered post-natal epileptic seizures, reflecting a profound impairment of GABAergic neuron maturation in different brain areas. Analysis of transcriptome and TRα1 cistrome also allowed us to identify a small set of genes, the transcription of which is upregulated by TRα1 in GABAergic neurons during post-natal maturation of the striatum and which probably play an important role during neurodevelopment. Thus, our results point to GABAergic neurons as direct targets of thyroid hormone during brain development and suggest that many defects seen in hypothyroid brains may be secondary to GABAergic neuron malfunction.
The invasion of de-differentiating cancer cells into hierarchical tissues
Authors: Zhou Da , Luo Yue , Dingli David , Traulsen Arne
Published: March 2019

Many fast renewing tissues are characterized by a hierarchical cellular architecture, with tissue specific stem cells at the root of the cellular hierarchy and differentiating into a whole range of specialized cells. There is increasing evidence that tumors are structured in a very similar way, mirroring the hierarchical structure of the host tissue. In some tissues, differentiated cells can also revert to the stem cell phenotype, which increases the risk that cells that have already acquired mutations lead to long lasting clones in the tissue. Recently, the modelling community has paid special attention to the consequences of de-differentiation on cellular hierarchies. However, the adaptive significance of de-differentiation is still poorly understood and thus it is unclear under which circumstances de-differentiating cells will invade a tissue. To address this, we developed mathematical models to investigate how de-differentiation could be selected as an adaptive mechanism in the context of cellular hierarchies. We consider the cases of stepwise and jumpwise de-differentiation in this study. Our results show that the emergence of de-differentiation is driven by the combination of the properties of the cellular hierarchy and the de-differentiation pattern and derive thresholds for which de-differentiation is expected to emerge.
Karyotypic divergence confounds cellular phenotypes in large pharmacogenomic studies
Authors: Quevedo Rene , El-Hachem Nehme , Smirnov Petr , Safikhani Zhaleh , Pugh Trevor J. , Haibe-Kains Benjamin
Published: March 2019

Background

Somatic copy-number alterations that affect large genomic regions are a major source of genomic diversity in cancer and can impact cellular phenotypes. Clonal heterogeneity within cancer cell lines can affect phenotypic presentation, including drug response.

Methods

We aggregated and analyzed SNP and copy number profiles from six pharmacogenomic datasets encompassing 1,691 cell lines screened for 13 molecules. To look for sources of genotype and karyotype discordances, we compared SNP genotypes and segmental copy-ratios across 5 kb genomic bins. To assess the impact of genomic discordances on pharmacogenomic studies, we assessed gene expression and drug sensitivity data for compared discordant and concordant lines.

Results

We found 6/1,378 (0.4%) cell lines profiled in two studies to be discordant in both genotypic and karyotypic identity, 51 (3.7%) discordant in genotype, 97 (7.0%) discordant in karyotype, and 125 (9.1%) potential misidentifications. We highlight cell lines REH, NCI-H23 and PSN1 as having drug response discordances that may hinge on divergent copy-number q

Conclusions

Our study highlights the low level of misidentification as evidence of effective cell line authentication standards in recent pharmacogenomic studies. However, the proclivity of cell lines to acquire somatic copy-number variants can alter the cellular phenotype, resulting in a biological and predictable effects on drug sensitivity. These findings highlight the need for verification of cell line copy number profiles to inform interpretation of drug sensitivity data in biomedical studies.
Analytical guidelines to increase the value of citizen science data: using eBird data to estimate species occurrence
Authors: Johnston A , Hochachka WM , Strimas-Mackey ME , Ruiz Gutierrez V , Robinson OJ , Miller ET , Auer T , Kelling ST , Fink D
Published: March 2019

Citizen science data are valuable for addressing a wide range of ecological research questions, and there has been a rapid increase in the scope and volume of data available. However, data from large-scale citizen science projects typically present a number of challenges that can inhibit robust ecological inferences. These challenges include: species bias, spatial bias, and variation in effort.

To demonstrate addressing key challenges in analysing citizen science data, we use the example of estimating species distributions with data from eBird, a large semi-structured citizen science project. We estimate two widely applied metrics of species distributions: encounter rate and occupancy probability. For each metric, we assess the impact of data processing steps that either degrade or refine the data used in the analyses. We also test whether differences in model performance are maintained at different sample sizes.

Model performance improved when data processing and analytical methods addressed the challenges arising from citizen science data. The largest gains in model performance were achieved with: 1) the use of complete checklists (where observers report all the species they detect and identify); and 2) the use of covariates describing variation in effort and detectability for each checklist. Occupancy models were more robust to a lack of complete checklists and effort variables. Improvements in model performance with data refinement were more evident with larger sample sizes.

Here, we describe processes to refine semi-structured citizen science data to estimate species distributions. We demonstrate the value of complete checklists, which can inform the design and adaptation of citizen science projects. We also demonstrate the value of information on effort. The methods we have outlined are also likely to improve other forms of inference, and will enable researchers to conduct robust analyses and harness the vast ecological knowledge that exists within citizen science data.
Exploitation of the cooperative behaviours of anti-CRISPR phages
Authors: Chevallereau Anne , Meaden Sean , Fradet Olivier , Landsberger Mariann , Maestri Alice , Biswas Ambarish , Gandon Sylvain , van Houte Stineke , Westra Edze R.
Published: March 2019

Many bacteria encode CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats; CRISPR-associated) adaptive immune systems to protect themselves against their viruses (phages)1. To overcome resistance, phages have evolved anti-CRISPR proteins (Acr), which naturally vary in their potency to suppress the host immune system and avoid phage extinction2,3,4,5. However, these Acr-phages need to cooperate in order to overcome CRISPR-based resistance4,5: while many initial infections by Acr-phages are unsuccessful, they nonetheless lead to the production of Acr proteins, which generate immunosuppressed cells that can be successfully exploited by other Acr-phages in the population4,5. Here we test the prediction that phages lacking acr genes (Acr-negative phages) may exploit this cooperative behaviour6. We demonstrate that Acr-negative phages can indeed benefit from the presence of Acr-positive phages during pairwise competitions, but the extent of this exploitation depends on the potency of the Acr protein. Specifically, “strong” Acr proteins are more exploitable and benefit both phage types, whereas “weak” Acr proteins predominantly benefit Acr-positive phages only and therefore provide a greater fitness advantage during competition with Acr-negative phages. This work further helps to explain what defines the strength of an Acr protein, how selection acts on different Acr types in a phage community context, and how this can shape the dynamics of phage populations in natural communities.
Long-tailed macaques extract statistical information from repeated types of events to make rational decisions under uncertainty
Authors: Placì Sarah , Padberg Marie , Rakoczy Hannes , Fischer Julia
Published: March 2019

Human children and apes are proficient intuitive statisticians when making predictions from populations of objects to randomly drawn samples, whereas monkeys seem not to be. Statistical reasoning can also be investigated in tasks in which the probabilities of different possibilities must be inferred from relative frequencies of events, but little is known about the performance of nonhuman primates in such tasks. In the current study, we investigated whether long-tailed macaques extract statistical information from repeated types of events to make predictions under uncertainty. In each experiment, monkeys first experienced the probability of rewards associated with different factors separately. In a subsequent test trial, monkeys could then choose between the different factors presented simultaneously. In Experiment 1, we tested whether long-tailed macaques relied on probabilities and not on a comparison of absolute quantities to make predictions. In Experiment 2 and 3 we varied the nature of the predictive factors and the complexity of the covariation structure between rewards and factors. Results indicate that long-tailed macaques extract statistical information from repeated types of events to make predictions and rational decisions under uncertainty, in more or less complex scenarios. These findings suggest that, given the right input information, monkeys are intuitive statisticians.
The Life History Of Human Foraging: Cross-Cultural And Individual Variation
Authors: Koster Jeremy , Mcelreath Richard , Hill Kim , Yu Douglas , Shepard Glenn , Vliet Nathalie Van , Gurven Michael , Kaplan Hillard , Trumble Benjamin , Bird Rebecca Bliege , Bird Douglas , Codding Brian , Coad Lauren , Pacheco-Cobos Luis , Winterhalder Bruce , Lupo Karen , Schmitt Dave , Sillitoe Paul , Franzen Margaret , Alvard Michael , Venkataraman Vivek , Kraft Thomas , Endicott Kirk , Beckerman Stephen , Marks Stuart A. , Headland Thomas , Pangau-Adam Margaretha , Siren Anders , Kramer Karen , Greaves Russell , Reyes-García Victoria , Guèze Maximilien , Duda Romain , Fernández-Llamazares Álvaro , Gallois Sandrine , Napitupulu Lucentezza , Ellen Roy , Ziker John , Nielsen Martin R. , Ready Elspeth , Healey Christopher , Ross Cody
Published: March 2019

Human adaptation depends upon the integration of slow life history, complex production skills, and extensive sociality. Refining and testing models of the evolution of human life history and cultural learning will benefit from increasingly accurate measurement of knowledge, skills, and rates of production with age. We pursue this goal by inferring individual hunters’ of hunting skill gain and loss from approximately 23,000 hunting records generated by more than 1,800 individuals at 40 locations. The model provides an improved picture of ages of peak productivity as well as variation within and among ages. The data reveal an average age of peak productivity between 30 and 35 years of age, though high skill is maintained throughout much of adulthood. In addition, there is substantial variation both among individuals and sites. Within study sites, variation among individuals depends more upon heterogeneity in rates of decline than in rates of increase. This analysis sharpens questions about the co-evolution of human life history and cultural adaptation. It also demonstrates new statistical algorithms and models that expand the potential inferences drawn from detailed quantitative data collected in the field.
A comprehensive examination of Nanopore native RNA sequencing for characterization of complex transcriptomes
Authors: Soneson Charlotte , Yao Yao , Bratus-Neuenschwander Anna , Patrignani Andrea , Robinson Mark D. , Hussain Shobbir
Published: March 2019

A platform for highly parallel direct sequencing of native RNA strands was recently described by Oxford Nanopore Technologies (ONT); in order to assess overall performance in transcript-level investigations, the technology was applied for sequencing sets of synthetic transcripts as well as a yeast transcriptome. However, despite initial efforts it remains crucial to further investigate characteristics of ONT native RNA sequencing when applied to much more complex transcriptomes. Here we thus undertook extensive native RNA sequencing of polyA+ RNA from two human cell lines, and thereby analysed ~5.2 million aligned native RNA reads which consisted of a total of ~4.6 billion bases. To enable informative comparisons, we also performed relevant ONT direct cDNA- and Illumina-sequencing. We find that while native RNA sequencing does enable some of the anticipated advantages, key unexpected aspects hamper its performance, most notably the quite frequent inability to obtain full-length transcripts from single reads, as well as difficulties to unambiguously infer their true transcript of origin. While characterising issues that need to be addressed when investigating more complex transcriptomes, our study highlights that with some defined improvements, native RNA sequencing could be an important addition to the mammalian transcriptomics toolbox.
A consensus set of genetic vulnerabilities to ATR inhibition
Authors: Hustedt Nicole , Álvarez-Quilón Alejandro , McEwan Andrea , Yuan Jing Yi , Cho Tiffany , Koob Lisa , Hart Traver , Durocher Daniel
Published: March 2019

The response to DNA replication stress in eukaryotes is under the control of the ataxia-telangiectasia and Rad3-related (ATR) kinase. ATR responds to single-stranded (ss) DNA to stabilize distressed DNA replication forks, modulate DNA replication firing and prevent cells with damaged DNA or incomplete DNA replication from entering into mitosis. Furthermore, inhibitors of ATR are currently in clinical development either as monotherapies or in combination with agents that perturb DNA replication. To gain a genetic view of the cellular pathways requiring ATR kinase function, we mapped genes whose mutation causes hypersensitivity to ATR inhibitors with genome-scale CRISPR/Cas9 screens. We delineate a consensus set of 117 genes enriched in DNA replication, DNA repair and cell cycle regulators that promote survival when ATR kinase activity is suppressed. We validate 14 genes from this set and report genes not previously described to modulate response to ATR inhibitors. In particular we found that the loss of the POLE3/POLE4 proteins, which are DNA polymerase e accessory subunits, results in marked hypersensitivity to ATR inhibition. We anticipate that this 117-gene set will be useful for the identification of genes involved in the regulation of genome integrity, the characterization of new biological processes involving ATR, and may reveal biomarkers of ATR inhibitor response in the clinic.
T Cell Receptor Immunotherapy Drives Human Immunodeficiency Virus Evolution in Humanized Mice
Authors: Joglekar Alok V. , Swift Margaret , Leonard Michael T. , Jeppson John D. , Sandoval Salemiz , Baltimore David
Published: March 2019

T cell receptor mediated immunotherapy using engineered Hematopoietic Stem/Progenitor Cells leads to durable partial suppression of HIV in humanized mice. Sustained viral suppression is accompanied by viral evolution under selection pressure. This study highlights the potential for TCR immunotherapy and the need to target multiple epitopes.

Effective CD8+ T cell responses targeted to the KK10 epitope of HIV presented by HLA-B*27:05, a protective HLA allele, correlate with the ability to control infection without antiretroviral therapy (ART). Here, we report an immunotherapy approach using two B*27:05-KK10-specific T Cell Receptors (TCRs) isolated from HIV controllers. Immunocompromised mice engrafted with human Hematopoietic Stem/Progenitor Cells (HSPCs) encoding for the TCRs showed differentiation into functionally active engineered T cells. Following infection with HIV, both TCRs showed sustained, albeit modest, viral suppression over 32 weeks, accompanied by a concomitant increase in CD4+ T cells. Sequencing of viral quasi-species from the plasma of infected mice demonstrated clear evidence for viral evolution under selection pressure from the TCRs. The most commonly observed mutation in the KK10 epitope was L6M, which preserved viral fitness but showed attenuated recognition by the TCRs. These studies show that TCR-immunotherapy was able to suppress HIV infection long-term while driving HIV evolution in humanized mice.
Genetic structure is stronger across human-impacted habitats than among islands in the coralPorites lobata
Authors: Tisthammer Kaho H. , Forsman Zac H. , Toonen Robert J. , Richmond Robert H.
Published: March 2019

We examined genetic structure in the lobe coralPorites lobataamong pairs of highly variable and high-stress nearshore sites and adjacent less variable and less impacted offshore sites on the islands of Oʻahu and Maui, Hawai‘i. Using an analysis of molecular variance framework, we tested whether populations were more structured by geographic distance or environmental extremes. The genetic patterns we observed followed isolation by environment, where nearshore and adjacent offshore populations showed significant genetic structure at both locations (AMOVAFST= 0.04 ∼ 0.19,P< 0.001), but no significant isolation by distance between islands. In contrast, a third site with a less impacted nearshore site showed no significant structure. Strikingly, corals from the two impacted nearshore sites on different islands over 100km apart with similar environmentally stressful conditions were genetically closer (FST∼ 0, P = 0.733) than those within a single location less than 2 km apart (FST= 0.041∼0.079, P < 0.01). Our results suggest that ecological boundaries appear to play a strong role in forming genetic structure in the coastal environment, and that genetic divergence in the absence of geographical barriers to gene flow may be explained by disruptive selection across contrasting habitats.
Characterisation ofl(3)tbas a novel tumour suppressor allele ofDCP2inDrosophila melanogaster
Authors: Mishra Rakesh , Kunar Rohit , Mandal Lolitika , Alone Debasmita P , Chandrasekharan Shanti , Tiwari Anand Krishna , Mukherjee Ashim , Tapadia Madhu G , Roy Jagat Kumar
Published: March 2019

Mutants provide an excellent platform for the discovery and characterization of gene functions. The present communication is a pioneering treatise on a hitherto undescribed function of the gene coding for the mRNA decapping protein 2 (DCP2) inDrosophila melanogaster. DCP2, the gene coding for the mRNA decapping enzyme, has been studied in various model organisms in the light of maintenance of transcript abundance and stability but has never been implicated in tumourigenesis. Herein, we describe the mapping and characterization of a novel tumour suppressor allele ofDCP2(CG6169), which we named aslethal(3)tumorous brain[l(3)tb]. The homozygous mutant individuals show prolonged larval life, develop larval brain tumors and are lethal in the larval/pupal stages. The tumour is characterized by the presence of increased number of superficial neuroblasts, abnormal chromosomal condensation and causes overgrowth in the wing and the eye-antennal discs of the homozygous mutant larvae, all of which are rescued by the introduction of a functional copy ofDCP2in the mutant background, thereby establishing the causal role of the mutation and providing a genetic validation of the allelism. Our findings therefore ascribe a novel role of tumor suppression toDCP2besides its cognate function of mRNA decapping and thereby identify it as a potential candidate for future research on tumorigenesis.
Regional climate affects salmon lice dynamics, stage structure, and management
Authors: Hurford Amy , Wang Xiunan , Zhao Xiao-Qiang
Published: March 2019

Regional variation in climate can generate differences in population dynamics and stage structure. Where regional differences exist, the best approach to pest management may be region specific. Salmon lice are a stage structured marine copepod that parasitizes salmonids at aquaculture sites worldwide, and have fecundity, development, and mortality rates that depend on temperature and salinity. We show that in Atlantic Canada and Norway, where the oceans are relatively cold, salmon lice abundance decreases during the winter months, but ultimately increases from year-to-year, while in Ireland and Chile, where the oceans are warmer, the population size grows monotonically without any seasonal declines. In colder regions, during the winter the stage structure is dominated by the adult stage, which is in contrast to warmer regions where all stages are abundant year round. These differences translate into region specific recommendations for management: regions with slower population growth have lower critical stocking densities, and regions with cold winters have a seasonal dependence in the timing of follow-up chemotherapeutic treatments. Predictions of our salmon lice model agree with empirical data, and our approach provides a method to understand the effects of regional differences in climate on salmon lice dynamics and management.
Modeling non-genetic dynamics of cancer cell states measured by single-cell analysis: Uncovering bifurcations that explain why treatment either kills a cancer cell or makes it resistant
Authors: Huang S.
Published: March 2019

Single-cell transcriptomics offers a new vista on non-genetic tumor cell plasticity, a neglected aspect of cancer. The gene expression state of each cell is governed by the gene regulatory network which represents a high-dimensional non-linear dynamical system that generates multiple stable attractor states and undergoes destabilizing bifurcations, manifest as critical transitions. Modeling clonal cell population as statistical ensembles of the same dynamical system, a index IC is derived for detecting destabilization towards critical transitions in single-cell molecular profiles. Therapy-induced bifurcation explains why treatment backfires: a drug-treated cell is imposed the binary choice to either apoptose or become a cancer-stem cell.
A novel, dynein-independent mechanism focuses the endoplasmic reticulum around spindle poles in dividingDrosophilaspermatocytes
Authors: Karabasheva Darya , Smyth Jeremy T.
Published: March 2019

In dividing animal cells the endoplasmic reticulum (ER) concentrates around the poles of the spindle apparatus by associating with astral microtubules (MTs), and this association is essential for proper ER partitioning to progeny cells. The mechanisms that associate the ER with astral MTs are unknown. Because astral MT minus-ends are anchored by centrosomes at spindle poles, we tested the hypothesis that the MT minus-end motor dynein mediates ER concentration around spindle poles. Livein vivoimaging ofDrosophilaspermatocytes undergoing the first meiotic division revealed that dynein is required for ER concentration around centrosomes during interphase. In marked contrast, however, dynein suppression had no effect on ER association with astral MTs and concentration around spindle poles in early M-phase. Importantly though, there was a sudden onset of ER-astral MT association inDhc64CRNAi cells, revealing activation of an M-phase specific mechanism. ER redistribution to spindle poles also did not require non-claret disjunctional (ncd), the other knownDrosophilaMT minus-end motor, nor Klp61F, a MT plus-end motor that generates spindle poleward forces. Collectively, our results suggest that a novel, M-phase specific mechanism of ER-MT association that is independent of MT minus-end motors is required for proper ER partitioning in dividing cells.
Multivariate pattern classification on BOLD activation pattern induced by deep brain stimulation in motor, associative, and limbic brain networks
Authors: Cho Shinho , Min Hoon-Ki , Gibson William S. , In Myung-Ho , Lee Kendall H. , Jo Hang Joon
Published: March 2019

Functional magnetic resonance imaging (fMRI) concurrently conducted with the deep brain stimulation (DBS) has shown that diffuse BOLD activation occurred not only near stimulation locus, but in multiple brain networks, supporting that network-wide modulation would underlie its therapeutic effect. While the extent and pattern of activation varies depending on specific anatomical locus stimulated by DBS, some stimulation targets could induce similar activation pattern in cerebral cortex, albeit different therapeutic and adverse effects were yielded.

In order to characterize the unique network-level activation effects of three DBS targets (subthalamic nucleus, the globus pallidus internus, and the nucleus accumbens), we trained the pattern classifier with DBS-fMRI data from three stimulation groups (21 healthy swine), wherein five six seconds of electrical stimulation was conducted while gradient-echo echo planar imaging was on going. Then whole brain regions were systematically grouped into different size of network-of-interest and the classification accuracy for individual target region was quantitatively assessed. We demonstrated that the pattern classifier could successfully differentiate BOLD activation pattern of cortical and subcortical brain regions originated from each individual stimulation target. Moreover, the success rate of classification indicated that some brain regions evoked indistinguishable BOLD pattern, suggesting the presence of commonly activated regions, which was influenced by stimulating different DBS targets.

Our results provide an understanding of the biomarker of BOLD pattern that is associated with clinical effectiveness as well as an adverse effect associated to the stimulation. Further, we provide the proof-of-concept for multivariate pattern analysis that is capable of disentangling the complicated BOLD activation pattern, which cannot be readily achieved by a conventional univariate analysis.
MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells
Authors: Gad Helge , Mortusewicz Oliver , Rudd Sean G , Stolz Ailine , Amaral Nuno , Brautigham Lars , Pudelko Linda , Sanjiv Kumar , Kaldéren Christina , Jemth Ann-Sofie , Almlöf Ingrid , Visnes Torkild , Schultz Niklas , Boström Johan , Calderon Montano José Manuel , Hagenkort Anna , Groth Petra , Loseva Olga , Gokturk Camilla , Koolmeister Tobias , Wakchaure Prasad , Homan Evert , Ström Cecilia E , Scobie Martin , Bastians Holger , Berglund Ulrika Warpman , Helleday Thomas
Published: March 2019

BACKGROUND

We developed MTH1 inhibitors (MTH1i) TH588 and TH1579 showing broad anti-cancer activity, while structurally distinct MTH1i fail to kill cancer cells. Here, we describe a new role of MTH1 in mitosis and the detailed mechanism of action of TH1579 (karonudib) and other structurally distinct MTH1i.

MATERIALS AND METHODS

Cancer cell lines or zebrafish embryos were treated with MTH1i or siRNA targeting MTH1 and analysed primarily by live cell and immunofluorescence microscopy, survival assays, DNA fibre or COMET assays. MTH1 and tubulin interactions were analysedin vitrousing co-immunoprecipitation and tubulin polymerisation assays.

RESULTS

Here, we describe a mitotic role for the MTH1 protein, which binds to tubulin, is required for microtubule polymerisation, correct spindle assembly, mitosis progression and suppression reactive oxygen species (ROS) generation in mitosis. Potent MTH1i display differential abilities to break the MTH1-tubulin interaction and cause mitotic arrest, demonstrating 8-oxodGTPase and mitotic function of MTH1 are mechanistically distinct. TH588 and TH1579 have more profound effect on mitotic arrest than other MTH1i explained by additional direct inhibition of tubulin polymerisation. MTH1i only inhibiting 8-oxodGTPase activity synergize with mitotic poisons.

CONCLUSIONS

Efficient MTH1 have a dual mechanism of action: inhibiting mitosis (to generate ROS) and promoting 8-oxodGTP incorporation into DNA during mitotic replication, dependent on ROS generation. Direct inhibition of tubulin polymerisation of TH588 and TH1579 increase their ability to arrest cells and generate ROS in mitosis. Furthermore, non-cytotoxic MTH1 can become effective and increase incorporation of oxidised nucleotides into DNA when combined with sub-therapeutic concentrations of mitotic inhibitors or challenged directly by 8-oxodGTP.
XPO1 gene therapy restores cardiac function in rats with chronic induced myocardial infarction
Authors: García-Manzanares María , Gil-Cayuela Carolina , Martínez-Dolz Luis , González-Juanatey José Ramón , Lago Francisca , Portolés Manuel , Roselló-Lletí Esther , Rivera Miguel
Published: March 2019

Background

In previous studies, we showed that several nuclear-cytoplasmic transport molecules were closely related to ventricular dysfunction in human heart failure. Particularly, the transcriptomic signature of XPO1 was highly expressed and inversely related to left ventricular function in heart failure patients of ischemic etiology. Therefore, we hypothesized that in a rat model of myocardial infarction treated with AAV9-shXPO1, an improvement in the ventricular function after a follow-up period may be observed.

Methods

We induced myocardial infarction by coronary ligation in Sprague-Dawley rats (n=10), five of them received AAV9-shXPO1 treatment after four months and the other five infarcted rats did not receive any treatment. For non-failing controls, healthy Sham rats (n=5) received the placebo AAV9-scramble. Serial echocardiographic assessment was performed before, as well as, two and five months after intravenous injection.

Results

AAV9-shXPO1-treated rats showed improved fractional shortening (16.8 ± 2.8 vs 24.6 ± 4.1%, P<0.05) and LV systolic (5.10 ± 0.79 vs 3.52 ± 0.88mm, P<0.05) and diastolic (6.17 ± 0.95 vs 4.70 ± 0.93mm, P<0.05) diameters when comparing measurements obtained before and five months after AAV9 injection. We did not observe this improvement in untreated infarcted rats. Furthermore, EXP-1 levels in rats heart, brain, skeletal muscle, and liver were determined by western-blot and compared to controls in AAV9-shXPO1-treated rats. Lower levels of EXP-1 in cardiac tissue were observed (P<0.05).

Discussion

At five months follow-up, ischemic AAV9-shXPO1-treated rats showed partial recovery of LV myocardial function. No secondary symptoms attributable to AAV9-shXPO1 were observed in skeletal muscle, liver and brain.
Flow arrest in the plasma membrane
Authors: Chein Michael , Perlson Eran , Roichman Yael
Published: March 2019

The arrangement of receptors in the plasma membrane strongly affects the ability of a cell to sense its environment both in terms of sensitivity and in terms of spatial resolution. The spatial and temporal arrangement of the receptors is affected in turn by the mechanical properties and the structure of the cell membrane. Here we focus on characterizing the flow of the membrane in response to the motion of a protein embedded in it. We do so by measuring the correlated diffusion of extracellularly tagged transmembrane neurotrophin receptors TrkB and p75 on transfected neuronal cells. In accord with previous reports, we find that the motion of single receptors exhibits transient confinement to sub-micron domains. We confirm predictions based on hydrodynamics of fluid membranes, finding long-range correlations in the motion of the receptors in the plasma membrane. However, we discover that these correlations do not persist for long ranges, as predicted, but decay exponentially, with a typical decay length on the scale of the average confining domain size.
CNEr: a toolkit for exploring extreme noncoding conservation
Authors: Tan Ge , Polychronopoulos Dimitris , Lenhard Boris
Published: March 2019

Conserved Noncoding Elements (CNEs) are elements exhibiting extreme noncoding conservation in Metazoan genomes. They cluster around developmental genes and act as long-range enhancers, yet nothing that we know about their function explains the observed conservation levels. Clusters of CNEs coincide with topologically associating domains (TADs), indicating ancient origins and stability of TAD locations. This has suggested further hypotheses about the still elusive origin of CNEs, and has provided a comparative genomics-based method of estimating the position of TADs around developmentally regulated genes in genomes where chromatin conformation capture data is missing. To enable researchers in gene regulation and chromatin biology to start deciphering this phenomenon, we developedCNEr, a R/Bioconductor toolkit for large-scale identification of CNEs and for studying their genomic properties. We applyCNErto two novel genome comparisons - fruit fly vs tsetse fly, and two sea urchin genomes - and report novel insights gained from their analysis. We also show how to reveal interesting characteristics of CNEs by coupling CNEr with existing Bioconductor packages.CNEris available at Bioconductor (https://bioconductor.org/packages/CNEr/) and maintained at github (https://github.com/ge11232002/CNEr).
High Hes1 expression and resultant Ascl1 suppression regulate quiescent vs. active neural stem cells in the adult mouse brain
Authors: Sueda Risa , Imayoshi Itaru , Harima Yukiko , Kageyama Ryoichiro
Published: March 2019

Somatic stem/progenitor cells are active in embryonic tissues but quiescent in many adult tissues. The detailed mechanisms that regulate active versus quiescent stem cell states are largely unknown. In active neural stem cells, Hes1 expression oscillates and drives cyclic expression of the proneural gene Ascl1, which activates cell proliferation. Here, we found that in quiescent neural stem cells in the adult mouse brain, Hes1 levels are oscillatory, although the peaks and troughs are higher than those in active neural stem cells, causing Ascl1 expression to be continuously suppressed. Inactivation of Hes1 and its related genes up-regulates Ascl1 expression and increases neurogenesis. This causes rapid depletion of neural stem cells and premature termination of neurogenesis. Conversely, sustained Hes1 expression represses Ascl1, inhibits neurogenesis, and maintains quiescent neural stem cells. In contrast, induction of Ascl1 oscillations activates neural stem cells and increases neurogenesis in the adult mouse brain. Thus, Ascl1 oscillations, which normally depend on Hes1 oscillations, regulate the active state, while high Hes1 expression and resultant Ascl1 suppression promote quiescence in neural stem cells.
Integrative genomic analysis of peritoneal malignant mesothelioma: understanding a case with extraordinary chemotherapy response
Authors: Lund-Andersen Christin , Nakken Sigve , Nygård Ståle , Fromm Bastian , Aasheim Lars B. , Davidson Ben , Julsrud Lars , Abrahamsen Torveig W. , Kristensen Annette T. , Dybdahl Brit , Larsen Stein G. , Hovig Eivind , Flatmark Kjersti
Published: March 2019

Peritoneal malignant mesothelioma is a rare disease with a generally poor prognosis and poor response to chemotherapy. To improve survival there is a need for increased molecular understanding of the disease, including chemotherapy sensitivity and resistance. We here present an unusual case concerning a young woman with extensive peritoneal mesothelioma who had a remarkable response to palliative chemotherapy (platinum/pemetrexed). Tumor samples collected at surgery before and after treatment were analyzed on the genomic and transcriptional levels (exome sequencing, RNA-seq, and smallRNA-seq). Integrative analysis of single nucleotide and copy-number variants, mutational signatures, and gene expression was performed to provide a comprehensive picture of the disease. LATS1/2 were identified as the main mutational drivers together with homozygous loss of BAP1 and PBRM1, which also may have contributed to the extraordinary chemotherapy response. The presence of the S3 mutational signature is consistent with homologous recombination DNA repair defects due to BAP1 loss. Up-regulation of the PI3K/AKT/mTOR pathway after treatment, supported by deactivated PTEN through miRNA regulation, is associated with cancer progression and could explain chemotherapy resistance. The molecular profile suggests potential benefit from experimental targeting of PARP, EZH2, the PI3K/AKT/mTOR pathway and possibly also from immune checkpoint inhibition. In addition to providing the molecular background for this unusual case of peritoneal mesothelioma, the results show the potential value of integrative genomic analysis in precision medicine.