bluuebunny/crossref_metadata_2025 huggingface dataset:
Similarity and strength of glomerular odor representations define neural metric of sniff-invariant discrimination time
Authors: Bhattacharjee Anindya S. , Konakamchi Sasank , Turaev Dmitrij , Vincis Roberto , Nunes Daniel , Dingankar Atharva A. , Spors Hartwig , Carleton Alan , Kuner Thomas , Abraham Nixon M.
Published: June 2018

The olfactory environment is first represented by glomerular activity patterns in the olfactory bulb. It remained unclear, how these activity patterns intersect with sampling behavior to account for the time required to discriminate odors. Using different classes of volatile stimuli, we investigated glomerular activity patterns and sniffing behavior during olfactory decision-making. Mice discriminated monomolecular odorants and binary mixtures on a fast time scale and learned to increase their breathing frequency at a fixed latency after trial initiation, independent of odor identity. Relative to the increase in breathing frequency, monomolecular odorants were discriminated within 10-40 ms while binary mixtures required an additional 60-70 ms. Intrinsic imaging of odor-evoked glomerular activity maps in anesthetized and awake mice revealed that the Euclidean distance between glomerular patterns elicited by different odors, a measure of similarity and activation strength, was anti-correlated with discrimination time. Therefore, the similarity of glomerular patterns and their activation strengths, rather than sampling behavior, define the extent of neuronal processing required for odor discrimination, establishing a neural metric to predict olfactory discrimination time.
Overwhelming presence of non-food vegetation undermines the reliability of NDVI as a surrogate of forage abundance for a large herbivore in a tropical forest habitat
Authors: Gautam Hansraj , Arulmalar Evangeline , Kulkami Mihir R , Vidya TNC
Published: June 2018

The use of remotely-sensed vegetation indices has increased in wildlife studies but field-based support for their utility as a measure of forage availability largely comes from open-canopy habitats. In this paper, we assessed whether the popular vegetation index, NDVI, actually represents forage availability for Asian elephants in a southern Indian tropical forest. We found that the number of food species was a small percentage of all plant species, and the abundance of food species compared to total species abundance varied across different vegetation categories. NDVI was not a good measure of food abundance in any vegetation category partly because of a) small to moderate proportional abundances of food species relative to the total abundance of all species in that category (herb and shrub categories), b) abundant overstorey vegetation resulting in low correlations between NDVI and food abundance despite a high proportional abundance of food species and a concordance between total abundance and food species abundance (graminoid category), and c) the relevant variables measured and important as food at the ground level (count and GBH) not being related to primary productivity (trees and recruits). NDVI had a negative relationship with the total abundance of graminoids, which represent a bulk of elephant and other herbivore diet, because of the presence of other vegetation types and canopy cover that positively explained NDVI. We also found that spatially interpolated total graminoid abundance modelled from field data outperformed NDVI in predicting total graminoid abundance, although interpolation models of food graminoid species abundance were not satisfactory. Our results reject the utility of NDVI as a surrogate of elephant forage abundance in tropical forests with multistorey vegetation, a finding that has implications for studies of other herbivores in such habitats.
Combined quantification of intracellular (phospho-)proteins and transcriptomics from fixed single cells
Authors: Gerlach Jan. P. , van Buggenum Jessie A. G. , Tanis Sabine E.J. , Hogeweg Mark , Heuts Branco M. H. , Muraro Mauro J. , Elze Lisa , Rivello Francesca , Rakszewska Agata , van Oudenaarden Alexander , Huck Wilhelm T. S. , Stunnenberg Hendrik G. , Mulder Klaas W.
Published: June 2018

Environmental stimuli often lead to heterogeneous cellular responses and transcriptional output. We developed single-cell RNA and Immunodetection (RAID) to allow combined analysis the transcriptome and intracellular (phospho-)proteins from fixed single cells. RAID successfully recapitulated differentiation-state changes at the protein and mRNA level in human keratinocytes. Furthermore, we show that differentiated keratinocytes that retain high phosphorylated FAK levels, a feature associated with stem cells, also express a selection of stem cell associated transcripts. Our data demonstrates that RAID allows investigation of heterogenenous cellular responses to environmental signals at the mRNA and phospho-proteome level.
Disentangling the process of speciation using machine learning
Authors: Smith Megan L. , Carstens Bryan C.
Published: June 2018

Historically, investigations into the processes driving speciation have largely been isolated from systematic investigations into species limits. Recent advances in sequencing technology have led to a rapid increase in the availability of genomic data, and this, in turn, has led to the introduction of many novel methods for species delimitation. However, these methods have been limited to divergence-only scenarios and have not attempted to evaluate complex modes of speciation, such as those that include gene flow during early stages of divergence (sympatric speciation) or population size changes (founder effect speciation). To address this shortcoming, we introducedelimitR, an approach that enables biologists to infer species boundaries and evaluate the demographic processes that may have led to speciation.delimitRuses the binned multidimensional Site Frequency Spectrum and a machine-learning algorithm (Random Forests) to compare speciation models. We use simulations to evaluate the accuracy ofdelimitR. When comparing models that include lineage divergence and gene flow for three populations, error rates are near zero with recent divergence times (<100,000 generations) and a modest number of Single Nucleotide Polymorphisms (SNPs; 1,500). When applied to a more complex model set (including divergence, gene flow, and population size changes), error rates are moderate (~0.15 with 10,000 SNPs), and misclassifications are generally between highly similar models. We also evaluate the utility ofdelimitRusing three previously published datasets and find results that corroborate previous findings. Our analyses indicate thatdelimitRcan serve as an important conceptual bridge uniting various investigations into the process of speciation.
The ‘filtering’ metaphor revisited: competition and environment jointly structure invasibility and coexistence
Authors: Germain Rachel M. , Mayfield Margaret M. , Gilbert Benjamin
Published: June 2018

‘Filtering’, or the reduction in species diversity that occurs because not all species can persist in all locations, is thought to unfold hierarchically, at large scales due to the environment and at small scales due to competition. However, the ecological effects of competition and the environment are not independent, and observational approaches preclude investigation into their interplay. We use a demographic approach with 30 plant species to experimentally test (i) the effect of competition on species persistence in two soil moisture environments, and (ii) the effect of environmental conditions on the mechanisms underlying competitive coexistence. We find that competitors cause differential persistence of species across environments even when these effects are lacking in the absence of competition, and that the traits that determine persistence depend on the competitive environment. Changing environmental conditions generated idiosyncratic effects on coexistence outcomes, increasing competitive exclusion of some species while promoting coexistence of others. Our results highlight the importance of considering environmental filtering in light of, rather than in isolation from, competition, and challenge community assembly models and approaches to projecting future species distributions.
Solution and gas-phase modifiers effect on heme proteins environment and conformational space
Authors: Butcher D. , Miksovska J. , Ridgeway M. E. , Park M. A. , Fernandez-Lima F.
Published: June 2018

The molecular environment is known to impact the secondary and tertiary structure of biomolecules, shifting the equilibrium between different conformational and oligomerization states. In the present study, the effect of solution additives and gas-phase modifiers on the molecular environment of two common heme proteins, bovine cytochrome c and equine myoglobin, is investigated as a function of the time after desolvation (e.g., 100 - 500 ms) using trapped ion mobility spectrometry – mass spectrometry. Changes in the mobility profiles are observed depending on the starting solution composition (i.e., in aqueous solution at neutral pH or in the presence of organic content: methanol, acetone, or acetonitrile) depending on the protein. In the presence of gas-phase modifiers (i.e., N2containing methanol, acetone, or acetonitrile), a shift in the mobility profiles driven by the gas-modifier mass and size and changes in the relative abundances and number of IMS bands are observed. We attribute these changes in the mobility profiles in the presence of gas-phase modifiers to a clustering/declustering mechanism by which organic molecules adsorb to the protein ion surface and lower energetic barriers for interconversion between conformational states, thus redefining the free energy landscape and equilibria between conformers. These structural biology experiments open new avenues for manipulation and interrogation of biomolecules in the gas-phase with the potential to emulate a large suite of solution conditions, ultimately including conditions that more accurately reflect a variety of intracellular environments.
Recommendations to address uncertainties in environmental risk assessment using toxicokinetics-toxicodynamics models
Authors: Baudrot Virgile , Charles Sandrine
Published: June 2018

ABSTRACT

Providing reliable environmental quality standards (EQSs) is a challenging issue in environmental risk assessment (ERA). These EQSs are derived from toxicity endpoints estimated from dose-response models to identify and characterize the environmental hazard of chemical compounds such as those released by human activities. These toxicity endpoints include the classicalx% effect/lethal concentrations at a specific timet(EC/LC(x,t)) and the new multiplication factors applied to environmental exposure profiles leading tox% effect reduction at a specific timet(MF(x,t), or denotedLP(x,t) by the EFSA). However, classical dose-response models used to estimate toxicity endpoints have some weaknesses, such as their dependency on observation time points, which are likely to differ between species (e.g., experiment duration). Furthermore, real-world exposure profiles are rarely constant over time, which makes the use of classical dose-response models difficult and compromises the derivation ofMF(x,t). When dealing with survival or immobility toxicity test data, these issues can be overcome with the use of the general unified threshold model of survival (GUTS), a toxicokinetics-toxicodynamics (TKTD) model that provides an explicit framework to analyse both time- and concentration-dependent data sets as well as obtain a mechanistic derivation ofEC/LC(x,t) andMF(x,t) regardless of x and at any time t of interest. In addition, the assessment of a risk is inherently built upon probability distributions, such that the next critical step for ERA is to characterize the uncertainties of toxicity endpoints and, consequently, those of EQSs. With this perspective, we investigated the use of a Bayesian framework to obtain the uncertainties from the calibration process and to propagate them to model predictions, includingLC(x,t) andMF(x,t) derivations. We also explored the mathematical properties ofLC(x,t) andMF(x,t) as well as the impact of different experimental designs to provide some recommendations for a robust derivation of toxicity endpoints leading to reliable EQSs: avoid computingLC(x,t) andMF(x,t) for extremexvalues (0 or 100%), where uncertainty is maximal; computeMF(x,t) after a long period of time to take depuration time into account and test survival under few correlated and uncorrelated pulses of the contaminant in terms of depuration.
Seed Genome Hypomethylated Regions Are Enriched In Transcription Factor Genes
Authors: Chen Min , Lin Jer-Young , Hur Jungim , Pelletier Julie M. , Baden Russell , Pellegrini Matteo , Harada John J. , Goldberg Robert B.
Published: June 2018

The precise mechanisms that control gene activity during seed development remain largely unknown. Previously, we showed that several genes essential for seed development, including those encoding storage proteins, fatty acid biosynthesis enzymes, and transcriptional regulators, such as ABI3 and FUS3, are located within hypomethylated regions of the soybean genome. These hypomethylated regions are similar to the DNA methylation valleys (DMVs), or canyons, found in mammalian cells. Here, we address the question of the extent to which DMVs are present within seed genomes, and what role they might play in seed development. We scanned soybean and Arabidopsis seed genomes from post-fertilization through dormancy and germination for regions that contain < 5% or < 0.4% bulk methylation in CG-, CHG-, and CHH-contexts over all developmental stages. We found that DMVs represent extensive portions of seed genomes, range in size from 5 to 76 kb, are scattered throughout all chromosomes, and are hypomethylated throughout the plant life cycle. Significantly, DMVs are enriched greatly in transcription factor genes, and other developmental genes, that play critical roles in seed formation. Many DMV genes are regulated with respect to seed stage, region, and tissue - and contain H3K4me3, H3K27me3, or bivalent marks that fluctuate during development. Our results indicate that DMVs are a unique regulatory feature of both plant and animal genomes, and that a large number of seed genes are regulated in the absence of methylation changes during development - probably by the action of specific transcription factors and epigenetic events at the chromatin level.

Significance

We scanned soybean and Arabidopsis seed genomes for hypomethylated regions, or DNA Methylation Valleys (DMVs), present in mammalian cells. A significant fraction of seed genomes contain DMV regions that have < 5% bulk DNA methylation, or, in many cases, no detectable DNA methylation. Methylation levels of seed DMVs do not vary detectably during seed development with respect to time, region, and tissue, and are present prior to fertilization. Seed DMVs are enriched in transcription factor genes and other genes critical for seed development, and are also decorated with histone marks that fluctuate with developmental stage, resembling in significant ways their animal counterparts. We conclude that many genes playing important roles in seed formation are regulated in the absence of detectable DNA methylation events, and suggest that selective action of transcriptional activators and repressors, as well as chromatin epigenetic events play important roles in making a seed - particularly embryo formation.
The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungusCryptococcus neoformans.
Authors: Caza Mélissa , Hu Guanggan , Neilson Eric David , Cho Minsu , Jung Won Hee , Kronstad James W.
Published: June 2018

The battle for iron between invading microorganisms and mammalian hosts is a pivotal determinant of the outcome of infection. The pathogenic fungus,Cryptococcus neoformans, employs multiple mechanisms to compete for iron during cryptococcosis, a disease primarily of immunocompromised hosts. In this study, we examined the role of endocytic trafficking in iron uptake by characterizing a mutant defective in the Sec1/Munc18 (SM) protein Vps45. This protein is known to regulate the machinery for vesicle trafficking and fusion via interactions with SNARE proteins. As expected, avps45deletion mutant was impaired in endocytosis and showed sensitivity to trafficking inhibitors. The mutant also showed poor growth on iron-limited media and a defect in transporting the Cfo1 ferroxidase of the high-affinity iron uptake system from the plasma membrane to the vacuole. Remarkably, we made the novel observation that Vps45 also contributes to mitochondrial function in that a Vps45-Gfp fusion protein associated with mitotracker, and avps45mutant showed enhanced sensitivity to inhibitors of electron transport complexes as well as changes in mitochondrial membrane potential. Consistent with mitochondrial function, thevps45mutant was impaired in calcium homeostasis. To assess the relevance of these defects for virulence, we examined cell surface properties of thevps45mutant and found increased sensitivity to agents that challenge cell wall integrity and antifungal drugs. A change in cell wall properties was consistent with our observation of altered capsule polysaccharide attachment, and with attenuated virulence in a mouse model of cryptococcosis. Overall, our studies reveal a novel role for Vps45-mediated trafficking for iron uptake, mitochondrial function and virulence.
A Genome-Wide Association Study Reveals a Novel Regulator of Ovule Number and Fertility inArabidopsis thaliana
Authors: Yuan Jing , Kessler Sharon A.
Published: June 2018

Ovules contain the female gametophytes which are fertilized during pollination to initiate seed development. Thus, the number of ovules that are produced during flower development is an important determinant of seed crop yield and plant fitness. Mutants with pleiotropic effects on development often alter the number of ovules, but specific regulators of ovule number have been difficult to identify in traditional mutant screens. We used natural variation in Arabidopsis accessions to identify new genes involved in the regulation of ovule number. The ovule numbers per flower of 189 Arabidopsis accessions were determined and found to have broad phenotypic variation that ranged from 39 ovules to 84 ovules per pistil. Genome-Wide Association tests revealed several genomic regions that are associated with ovule number. T-DNA insertion lines in candidate genes from the most significantly associated loci were screened for ovule number phenotypes. TheNEW ENHANCER of ROOT DWARFISM (NERD1)gene was found to have pleiotropic effects on plant fertility that include regulation of ovule number and both male and female gametophyte development. Overexpression of NERD1 increased ovule number per fruit in a background-dependent manner and more than doubled the total number of flowers produced in all backgrounds tested, indicating that manipulation of NERD1 levels can be used to increase plant productivity.

Author Summary

Ovules are the precursors of seeds in flowering plants. Each ovule contains an egg cell and a central cell that fuse with two sperm cells during double fertilization to generate seeds containing an embryo and endosperm. The number of ovules produced during flower development determines the maximum number of seeds that can be produced by a flower. In this paper, we used natural variation inArabidopsis thalianaaccessions to identify regions of the genome that are associated with ovule number. Polymorphisms in the plant-specific NERD1 gene on chromosome 3 were significantly associated with ovule number. Mutant and overexpression analyses revealed thatNERD1is a positive regulator of ovule number, lateral branching, and flower number in Arabidopsis. Manipulation of NERD1 expression levels could potentially be used to increase yield in crop plants.
Vimentin filaments interact with the mitotic cortex allowing normal cell division
Authors: Duarte Sofia , Viedma-Poyatos Álvaro , Navarro-Carrasco Elena , Martínez Alma E. , Pajares María A. , Pérez-Sala Dolores
Published: June 2018

The vimentin network displays remarkable plasticity to support basic cellular functions. Here, we show that in several cell types vimentin filaments redistribute to the cell periphery during mitosis, forming a robust scaffold interwoven with cortical actin and affecting the mitotic cortex properties. Importantly, the intrinsically disordered tail domain of vimentin is essential for this redistribution, which allows normal mitotic progression. A tailless vimentin mutant forms curly bundles, which remain entangled with dividing chromosomes leading to mitotic catastrophes or asymmetric partitions. Serial deletions of the tail domain induce increasing impairments of cortical association and mitosis progression. Disruption of actin, but not of microtubules, mimics the impact of tail deletion. Pathophysiological stimuli, including HIV-protease and lipoxidation, induce similar alterations. Interestingly, filament integrity is dispensable for cortical association, which also occurs in vimentin particles. These results unveil novel implications of vimentin dynamics in cell division by means of its interplay with the mitotic cortex.
EnsembleCNV: An ensemble machine learning algorithm to identify and genotype copy number variation using SNP array data
Authors: Zhang Zhongyang , Cheng Haoxiang , Hong Xiumei , Narzo Antonio F. Di , Franzen Oscar , Peng Shouneng , Ruusalepp Arno , Kovacic Jason C. , Bjorkegren Johan LM , Wang Xiaobin , Hao Ke
Published: June 2018

The associations between diseases/traits and copy number variants (CNVs) have not been systematically investigated in genome-wide association studies (GWASs), primarily due to a lack of robust and accurate tools for CNV genotyping. Herein, we propose a novel ensemble learning framework, ensembleCNV, to detect and genotype CNVs using single nucleotide polymorphism (SNP) array data. EnsembleCNV a) identifies and eliminates batch effects at raw data level; b) assembles individual CNV calls into CNV regions (CNVRs) from multiple existing callers with complementary strengths by a heuristic algorithm; c) re-genotypes each CNVR with local likelihood model adjusted by global information across multiple CNVRs; d) refines CNVR boundaries by local correlation structure in copy number intensities; e) provides direct CNV genotyping accompanied with confidence score, directly accessible for downstream quality control and association analysis. Benchmarked on two large datasets, ensembleCNV outperformed competing methods and achieved a high call rate (93.3%) and reproducibility (98.6%), while concurrently achieving high sensitivity by capturing 85% of common CNVs documented in the 1000 Genomes Project. Given this CNV call rate and accuracy, which are comparable to SNP genotyping, we suggest ensembleCNV holds significant promise for performing genome-wide CNV association studies and investigating how CNVs predispose to human diseases.
Using human sequencing to guide craniofacial research
Authors: Liegel Ryan P. , Finnerty Erin , Ward Lauren , DiStasio Andrew , Hufnagel Robert B. , Saal Howard M. , Prows Cynthia A. , Stottmann Rolf
Published: June 2018

A recent convergence of technological innovations has re-energized the ability to apply genetics to research in human craniofacial development. Next-generation exome and whole genome sequencing have dropped in price significantly making it relatively trivial to sequence and analyze patients and families with congenital craniofacial anomalies. A concurrent revolution in genome editing with the use of the CRISPR-Cas9 system enables the rapid generation of animal models, including mouse, which can precisely recapitulate human variants. Here we summarize the choices currently available to the research community. We illustrate this approach with the study of a family with a novel craniofacial syndrome with dominant inheritance pattern. The genomic analysis suggest a causal variant in AMOTL1 which we modeled in mice. We also made a novel deletion allele of Amotl1. Our results indicate that Amotl1 is not required in the mouse for survival to weaning. Mice carrying the variant identified in the human sequencing studies, however, do not survive to weaning in normal ratios. The cause of death is not understood for these mice complicating our conclusions about the pathogenicity in the index patient. Thus, we highlight some of the powerful opportunities and confounding factors confronting current craniofacial genetic research.
Stoichiometry and Mobility Switching of a Morphogenetic Protein in Live Differentiating Cells
Authors: Wollman Adam J. M. , Muchová Katarína , Chromiková Zuzana , Wilkinson Anthony J. , Barák Imrich , Leake Mark C.
Published: June 2018

Spore formation following asymmetric cell division in Bacillus subtilis offers a model system to study development, morphogenesis and signal transduction in more complex organisms. Extensive biochemical and genetic details of its sporulation factors are known, however, the molecular mechanisms by which asymmetry is generated remain unclear. A crucial membrane phosphatase, SpoIIE, couples gene regulation to morphology changes, but how it performs different functions dependent on cell stage is unknown. We addressed this puzzle using high-speed single-molecule fluorescence microscopy on live B. subtilis expressing genomically encoded SpoIIE fluorescent protein fusions during sporulation. Copy number analysis indicated a few tens of SpoIIE at sporulation onset increasing to 400-600 molecules per cell following asymmetric cell division with up to 30% greater proportion in the forespore, corresponding to a concentration enhancement in the smaller forespore sufficient for differential dephosphorylation of an anti-sigma factor antagonist and activation of the forespore specific transcription factor, σF. Step-wise photobleach analysis indicates that SpoIIE forms tetramers capable of reversible oligomerisation to form clusters correlated with stage-specific functions. Specifically, low mobility SpoIIE clusters which initially localize to the asymmetric septum are released as mobile SpoIIE clusters around the forespore when phosphatase activity is manifested. SpoIIE is subsequently recaptured at the septum in a SpoIIQ-dependent manner. After mother cell engulfment of the forespore, SpoIIE is released as a mix of higher mobility clusters and tetramers. Our findings suggest that additional information captured in the changing state of multimerization and mobility enable one protein to perform different roles at different cell stages.

Significance/impact

Certain bacteria undergo sporulation involving cells dividing asymmetrically. A crucial protein SpoIIE facilitates this morphological asymmetry and directly links it to asymmetry in gene expression. Here, we used specialized light microscopy, capable of observing single molecules, plus biophysics, genetics and biochemical tools, to monitor SpoIIE in single living bacteria in real time, allowing us to count how many molecules are present in different cell regions, and how mobile they are. We find that SpoIIE clusters and moves depending on development stages, indicating that it has different roles depending on other binding proteins and their cellular locations. Our results suggest that changes in molecular stoichiometry and mobility may be used as switches in more complex cell processes.
Evidence that recurrent Group A streptococcus tonsillitis is an immunosusceptibility disease involving antibody deficiency and aberrant Tfh cells
Authors: Dan Jennifer M. , Havenar-Daughton Colin , Kendric Kayla , Kaushik Kirti , Rosales Sandy L. , Anderson Erika , LaRock Christopher , Vijayanand Pandurangan , Seumois Gregory , Layfield David , Cutress Ramsey , Ottensmier Christian , Lindestam Arlehamn Cecilia , Sette Alessandro , Nizet Victor , Bothwell Marcella , Brigger Matthew , Crotty Shane
Published: June 2018

One Sentence Summary

Recurrent tonsillitis is a multifactorial disease associated with an aberrant tonsillar germinal center response to Group A Streptococcus.

Recurrent Group A Streptococcus (GAS) tonsillitis (RT) is a common indication for pediatric tonsillectomy. ‘Strep throat’ is highly prevalent among children; yet, it is unknown why some children develop RT. To gain insights into this classic childhood disease, we performed phenotypic, genotypic, and functional studies on pediatric GAS RT and non-RT tonsils. We observed significantly smaller germinal centers in GAS RT tonsils, and underrepresentation of GAS-specific germinal center follicular helper (GC Tfh) CD4+T cells. RT children exhibited reduced antibody responses to GAS virulence factor SpeA. Risk and protective HLA Class II alleles for RT were identified. Finally, SpeA induced granzyme B+GC Tfh cells in RT tonsils that had capacity to kill B cells. Together, these observations suggest that RT susceptibility can occur due to genetic differences that can result in aberrant GC Tfh cells and poor antibody responses to GAS SpeA.
Heading Perception Depends on Time-Varying Evolution of Optic Flow
Authors: Burlingham Charlie S. , Heeger David J.
Published: June 2018

There is considerable support for the hypothesis that perception of heading in the presence of rotation is mediated by instantaneous optic flow. This hypothesis, however, has never been tested. We introduce a novel method, termed “non-varying phase motion,” for generating a stimulus that conveys a single instantaneous optic flow field, even though the stimulus is presented for an extended period of time. In this experiment, observers viewed stimulus videos and performed a forced choice heading discrimination task. For non-varying phase motion, observers made large errors in heading judgments. This suggests that instantaneous optic flow is insufficient for heading perception in the presence of rotation. These errors were mostly eliminated when the velocity of phase motion was varied over time to convey the evolving sequence of optic flow fields corresponding to a particular heading. This demonstrates that heading perception in the presence of rotation relies on the time-varying evolution of optic flow. We hypothesize that the visual system accurately computes heading, despite rotation, based on optic acceleration, the temporal derivative of optic flow.
Malaria and Burkitt’s Lymphoma: An In Silico Analysis of Gene Expression Links between Malaria and Burkitt’s Lymphoma and Potential Anticancer Activity of Artemisinin Derivatives
Authors: Elsayed Inas , Amin Mutaz , Abdel Hamid Muzamil Mahdi , Wang Xiaosheng , Rizig Mie
Published: June 2018

Background

Burkitt’s lymphoma (BL) is an aggressive form of B-cell non-Hodgkin lymphoma. Endemic subtype of the disease showed a remarkable statistical and epidemiological association with malaria infection. Despite the numerous studies performed to explain this association; molecular mechanisms underlie such coincidence still remain unclear. Dissecting molecular mechanisms which link Malaria infection and Burkitt’s lymphoma can provide insights about reported anticancer action of certain antimalarial drugs, namely artemisinin derivatives.

Methods

Here we applied an integrative approach to investigate for potential links between malaria infection and endemic Burkitt’s lymphoma regarding their gene expression, and further explore common molecular mechanisms through which artemisinin compounds might act in endemic Burkitt’s lymphoma. Using gene expression data of malaria (Plasmodium falciparum infected erythroblasts) and endemic Burkitt’s lymphoma from Gene Expression Omnibus database, expression patterns in the two conditions were examined through clustering analysis using Self Organizing Maps, and then by significance testing of differentially expressed genes in each condition followed by Functional annotation using Gene Ontology clustering and Pathways analysis.

Results

Clustering analysis identified a significant overlap between the expression patterns in endemic Burkitt’s lymphoma and Plasmodium falciparum infected cells. Four out of the 12 identified clusters contained genes with similar expression patterns in both conditions. Differential expression analysis identified 1689 genes as significantly differentially expressed in endemic Burkitt’s lymphoma and 405 in malaria. Those genes were found to be related to important Gene Ontology terms and pathways. Interestingly 65% of the identified pathways in Malaria were overlapped with those identified in endemic Burkitt’s lymphoma. Several of these pathways reported to be related to actions of artemisinin derivatives.

Conclusion

Our In-silico analysis showed a significant molecular convergence between endemic Burkitt’s lymphoma and malaria. A number of 43pathways which demonstrated enrichment in tumour were shared with Plasmodium falciparum infected erythrocytes. Such pathways represent potential targets for antimalarial drugs to exert therapeutic effects in such malignancy.
Megaphage infect Prevotella and variants are widespread in gut microbiomes
Authors: Devoto Audra E. , Santini Joanne M. , Olm Matthew R. , Anantharaman Karthik , Munk Patrick , Tung Jenny , Archie Elizabeth A. , Turnbaugh Peter J. , Seed Kimberley D. , Blekhman Ran , Aarestrup Frank M. , Thomas Brian C. , Banfield Jillian F.
Published: June 2018

Bacteriophage (phage) dramatically shape microbial community composition, redistribute nutrients via host lysis, and drive evolution through horizontal gene transfer. Despite their importance, much remains to be learned about phage in the human microbiome. We investigated gut microbiomes of humans from Bangladesh and Tanzania, two African baboon social groups, and Danish pigs, and report that many contain phage belonging to a clade with genomes >540 kb in length, the largest yet reported in the human microbiome and close to the maximum size ever reported for phage. We refer to these as Lak phage. CRISPR spacer targeting indicates that the Lak phage infect bacteria of the genus Prevotella. We manually curated to completion 15 distinct Lak phage genomes recovered from metagenomes. The genomes display several interesting features, including use of an alternative genetic code, large intergenic regions that are highly expressed, and up to 35 putative tRNAs, some of which contain enigmatic introns. Different individuals have distinct phage genotypes, and shifts in variant frequencies over consecutive sampling days reflect changes in relative abundance of phage sub-populations. Recent homologous recombination has resulted in extensive genome admixture of nine baboon Lak phage populations. We infer that Lak phage are widespread in gut communities that contain Prevotella species, especially in individuals in the developing world, and conclude that megaphage, with fascinating and underexplored biology, may be common but largely overlooked components of human and animal gut microbiomes.
Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons
Authors: Bolze Alexandre , Boisson Bertrand , Bosch Barbara , Antipenko Alexander , Bouaziz Matthieu , Sackstein Paul , Chaker-Margot Malik , Barlogis Vincent , Briggs Tracy , Colino Elena , Elmore Aurora C. , Fischer Alain , Genel Ferah , Hewlett Angela , Jedidi Maher , Kelecic Jadranka , Krüger Renate , Ku Cheng-Lung , Kumararatne Dinakantha , Loughlin Sam , Lefevre-Utile Alain , Mahlaoui Nizar , Markus Susanne , Garcia Juan-Miguel , Nizon Mathilde , Oleastro Matias , Pac Malgorzata , Picard Capucine , Pollard Andrew J. , Rodriguez-Gallego Carlos , Thomas Caroline , Von Bernuth Horst , Worth Austen , Meyts Isabelle , Risolino Maurizio , Selleri Licia , Puel Anne , Klinge Sebastian , Abel Laurent , Casanova Jean-Laurent
Published: June 2018

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here eleven new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5’-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that six of eighteen (33%) protein-coding mutations and the two (100%) 5’-UTR mutations display incomplete penetrance. Three mutations were identified in 2 independent kindreds, due to a hotspot or a founder effect. Lastly, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.
Think zinc: Role of zinc poisoning in the intraphagosomal killing of bacteria by the amoeba Dictyostelium
Authors: Barisch Caroline , Kalinina Vera , Lefrançois Louise H. , Appiah Joddy , Soldati Thierry
Published: June 2018

Professional phagocytes have developed an extensive repertoire of autonomous immunity strategies to ensure killing of bacteria. Besides phagosome acidification and the generation of reactive oxygen species, deprivation of nutrients and the lumenal accumulation of toxic metals are essential to kill ingested bacteria or inhibit growth of intracellular pathogens. We use the soil amoeba Dictyostelium discoideum, a professional phagocyte that digests bacteria for nutritional purposes, to decipher the role of zinc poisoning during phagocytosis of non-pathogenic bacteria and visualize the temporal and spatial dynamics of compartmentalized, free zinc using fluorescent probes. Immediately after particle uptake, zinc is delivered to phagosomes by fusion with “zincosomes” of endosomal origin, but also by the action of one or more zinc transporters. We localize the four Dictyostelium ZnT transporters to endosomes, the contractile vacuole and the Golgi apparatus, and study the impact of znt knockouts on zinc homeostasis. Finally, we show that zinc is delivered into the lumen of Mycobacterium smegmatis-containing vacuoles, and that Escherichia coli deficient in the zinc efflux P1B-type ATPase ZntA is killed faster than wild type bacteria.

Summary statement

Metal poisoning is one of the bactericidal strategies of macrophages. Here, we describe the dynamics of free Zn and the role of Zn transporters during phagocytosis in Dictyostelium.
Difference in accumulation pattern of the allergens within the same PR10 family in transgenic rice
Authors: Takaiwa Fumio , Ogo Yuko , Wakasa Yuhya
Published: June 2018

Apple food allergen Mal d 1 and birch pollen allergen Bet v 1 belong to the same pathogen related protein 10 (PR10) family. When each of these allergens was expressed as a secretory protein by fusion with the GFP reporter in transgenic rice by ligating an N terminal signal peptide and a C terminal KDEL ER retention signal under the control of the maize ubiquitin constitutive promoter, the GFP:Mald1 highly accumulated in various tissues, whereas the accumulation level of GFP:Betv1 was remarkably reduced in vegetative tissues except for seed. Analysis by RT-PCR exhibited that there was little difference in transcript levels between them, indicating the involvement of post-transcriptional regulation. To investigate the cause of such difference in accumulation levels, deletion analysis of the Mal d 1 and domain swapping between them were carried out in transgenic rice. These results showed that the region between positions 41-90 in the Mal d 1 is predominantly implicated in higher level accumulation in vegetative tissues as well as seed compared with the Bet v 1. It is notable that GFP:Mald1 directed by the ubiquitin promoter is deposited in huge PBs in aleurone layer rather than starchy endosperm.

Highlight

Specific region of PR10 proteins is mainly implicated in their stability in vegetative tissues when expressed in transgenic rice.
Integral Gene Drives: an “operating system” for population replacement
Authors: Nash Alexander , Urdaneta Giulia Mignini , K. Beaghton Andrea , Hoermann Astrid , Aris Papathanos Philippos , Christophides George K. , Windbichler Nikolai
Published: June 2018

First generation CRISPR-based gene drives have now been tested in the laboratory in a number of organisms including malaria vector mosquitoes. A number of challenges for their use in the area-wide genetic control of vector-borne disease have been identified. These include the development of target site resistance, their long-term efficacy in the field, their molecular complexity, and the practical and legal limitations for field testing of both gene drive and coupled anti-pathogen traits. To address these challenges, we have evaluated the concept of Integral Gene Drive (IGD) as an alternative paradigm for population replacement. IGDs incorporate a minimal set of molecular components, including both the drive and the anti-pathogen effector elements directly embedded within endogenous genes – an arrangement which we refer to as gene “hijacking”. This design would allow autonomous and non-autonomous IGD traits and strains to be generated, tested, optimized, regulated and imported independently. We performed quantitative modelling comparing IGDs with classical replacement drives and show that selection for the function of the hijacked host gene can significantly reduce the establishment of resistant alleles in the population while hedging drive over multiple genomic loci prolongs the duration of transmission blockage in the face of pre-existing target-site variation. IGD thus has the potential to yield more durable and flexible population replacement traits.
Dynamic m6A methylation facilitates mRNA triaging to stress granules
Authors: Anders Maximilian , Chelysheva Irina , Goebel Ingrid , Trenkner Timo , Zhou Jun , Mao Yuanhui , Verzini Silvia , Qian Shu-Bing , Ignatova Zoya
Published: June 2018

Summary blurb

m6A-modification in the 5’ vicinity of the coding sequence of transcripts provides a selective mechanism for triaging mRNAs to stress granules and is mediated by YTHDF3 ‘reader’ protein.

Reversible post-transcriptional modifications on messenger RNA emerge as prevalent phenomena in RNA metabolism. The most abundant among them is N6-methyladenosine (m6A) which is pivotal for RNA metabolism and function, its role in stress response remains elusive. We have discovered that in response to oxidative stress, transcripts are additionally m6A-modified in their 5’ vicinity. Distinct from that of the translationally-active mRNAs, this methylation pattern provides a selective mechanism for triaging mRNAs from the translatable pool to stress-induced stress granules. These stress-induced newly methylated sites are selectively recognized by the YTH domain family 3 (YTHDF3) ‘reader’ protein, thereby revealing a new role for YTHDF3 in shaping the selectivity of stress response. Our findings describe a previously unappreciated function for RNA m6A modification in the oxidative-stress response and expand the breadth of physiological roles of m6A.
Genome-wide mapping reveals conserved and diverged R-loop activities in the unusual genetic landscape of the African trypanosome genome
Authors: Briggs Emma , Hamilton Graham , Crouch Kathryn , Lapsley Craig , McCulloch Richard
Published: June 2018

R-loops are stable RNA-DNA hybrids that have been implicated in transcription initiation and termination, as well as in telomere homeostasis, chromatin formation, and genome replication and instability. RNA Polymerase (Pol) II transcription in the protozoan parasite Trypanosoma brucei is highly unusual: virtually all genes are co-transcribed from multigene transcription units, with mRNAs generated by linked trans-splicing and polyadenylation, and transcription initiation sites display no conserved promoter motifs. Here, we describe the genome-wide distribution of R-loops in wild type mammal-infective T. brucei and in mutants lacking RNase H1, revealing both conserved and diverged functions. Conserved localisation was found at centromeres, rRNA genes and retrotransposon-associated genes. RNA Pol II transcription initiation sites also displayed R-loops, suggesting a broadly conserved role despite the lack of promoter conservation or transcription initiation regulation. However, the most abundant sites of R-loop enrichment were within the intergenic regions of the multigene transcription units, where the hybrids coincide with sites of polyadenylation and nucleosome-depletion. Thus, instead of functioning in transcription termination, most T. brucei R-loops act in a novel role, promoting RNA Pol II movement or mRNA processing. Finally, we show there is little evidence for correlation between R-loop localisation and mapped sites of DNA replication initiation.
Benzo(a)pyrene (B[a]P) and its adverse effects on male testis
Authors: Liu Wei , Gu Aihua
Published: June 2018

It has been proved that Benzo(a)pyrene (B[a]P) is mutagenic in somatic cells, whereas the adverse effect of BaP on male reproduction remains unclear. To investigate whether it can pass through the blood-testis barrier (BTB) and its potential reproductive toxicology and molecular mechanisms, mice were exposed to B[a]P (there are two doses, that is 13mg/kg body weight and 26 mg/kg body weight; three times per week) during 6 weeks and sacrificed 6 weeks after the final exposure to obtain B[a]P-exposed testis, blood and others. Electron microscopy analysis was performed to confirm whether the integrity of BTB and the ultra-structure changes in testes of B[a]P treated mice, which showed that the integrity of the BTB was disrupted, accompanied with the structure of sertoli cells seriously damaged, including the integrity of the nuclear membrane of the sertoli cells impaired and the basement membrane of the seminiferous tubules disrupted. X-ray imaging in vitro told us that BaP can overgo the BTB and gathered in the testis of mice. We found the significantly decreased expression of ZO-1, occludin, N-cadherin, vimentin and claudin-1 in the testes of B[a]P treated group by immunofluorescence detection. B[a]P induced BTB component protein decreased were also found in TM4 cells exposed to 5μmol/L B[a]P for 24h. We found a significantly decrease of testosterone level and a significantly increase of estrogen level in the serum of treated groups comparing with the control one by radioimmunoassay. TM4 cells, MLTC-1 cells and GC-2 cells was cultured with medium contains B[a]P. MTT Cell Proliferation and Cytotoxicity Assay, cell apoptosis analysis, FACScan analyzer, We observed apparent increase of TM4 and GC-2 cells apoptosis after expose to B[a]P for 24h. B[a]P induced TM4 cell, GC-2 cell and MLTC-1 cell G2/M phase cell arrest. In conclusion, these results suggested that BaP has an adverse impact on male reproduction, it can cross the blood-testis barrier and damage it, the component proteins of the BTB significantly decreased, it can also produce adverse impact on male germ cells.