bluuebunny/crossref_metadata_2025 huggingface dataset:
An empirical model to predict survival curve and relative biological effectiveness after helium and carbon ion irradiation based solely on the cell survival after photon irradiation
Authors: Flint David B. , Bright Scott J. , McFadden Conor H. , Konishi Teruaki , Ohsawa Daisuke , Kobayashi Alisa , Shaitelman Simona F. , Sawakuchi Gabriel O.
Published: June 2020

Purpose

To develop an empirical model to predict radiosensitivity and relative biological effectiveness (RBE) after helium (He) and carbon (C) ion irradiation with or without DNA repair inhibitors.

Methods

We characterized survival in eight human cancer cell lines exposed to 6 MV photons and to He- and C-ions with linear energy transfer (LET) values of 2.2-60.5 keV/μm to verify that the radiosensitivity parameters (D5%, D10%, D20%, D37%, D50%and SF2Gy) correlate linearly between photon and ion radiation with or without DNA-PKcs or ATR inhibitors. Then, we parameterized the LET response of the parameters governing these linear correlations up to LET values of 225 keV/μm using the data in the Particle Irradiation Data Ensemble (PIDE) v3.2 database, creating a model that predicts a cell’s ion radiosensitivity, RBE and ion survival curve for a given LET on the basis of the cell’s photon radiosensitivity. We then trained this model using the PIDE database as a training dataset, and validated it by predicting the radiosensitivity of the cell lines we exposed to He- and C- ions with LET ranging from 2.2-60.5 keV/μm.

Results

Radiosensitivity to ions depended linearly with radiosensitivity of photons in the range of investigated LET values and the slopes and intercepts of these linear relationships within the PIDE database vary exponentially and linearly, respectively. Our model predicted ion radiosensitivity (e.g., D10%) within 5.1–21.3%, RBED10%within 5.0-17.1%, and ion mean inactivation dose within 6.7-25.1% for He- and C-ion LET ranging from 2.2-60.5 keV/μm.

Conclusions

Radiosensitivity to He- and C-ions depend linearly with radiosensitivity to photons and can be used to predict ion radiosensitivity, RBE and cell survival curves for clinically relevant LET values from 2.2–60.5 keV/μm, with or without drug treatment.

We present a new empirical model capable of predicting clonogenic cell survival of cell lines exposed to helium and carbon ion beams. Our model is based on an observed linear correlation between radiosensitivity to ions and photons across a wide range of LET values. This linear correlation can be used to predict ion RBE, radiosensitivity, and the cell survival curve for a given LET all based on a cell’s photon survival curve.
Lineage-Specific Silencing ofPSAT1Induces Serine Auxotrophy and Sensitivity to Dietary Serine Starvation in Luminal Breast Tumors
Authors: Choi Bo-Hyun , Conger Kelly O. , Selfors Laura M. , Coloff Jonathan L.
Published: June 2020

A major challenge of targeting metabolism for cancer therapy is pathway redundancy, where multiple sources of critical nutrients can limit the effectiveness of some metabolism-targeted therapies. Here, we analyzed lineage-dependent gene expression in human breast tumors to identify differences in metabolic gene expression that may limit pathway redundancy and create therapeutic vulnerabilities. We found that the serine synthesis pathway genePSAT1is the most depleted metabolic gene in luminal breast tumors relative to basal tumors. Low PSAT1 preventsde novoserine biosynthesis and sensitizes luminal breast cancer cells to serine and glycine starvationin vitroandin vivo. ThisPSAT1expression disparity—which pre-exists in the putative cells-of-origin of basal and luminal tumors—is due to luminal-specific hypermethylation of thePSAT1gene. Together, our data demonstrates that luminal breast tumors are auxotrophic for serine and may be uniquely sensitive to dietary serine starvation.
Lung at a Glance: an integrative web toolset of lung ontology, imaging and single cell omics
Authors: Du Yina , Ouyang Weichen , Kitzmiller Joseph A , Guo Minzhe , Zhao Shuyang , Whitsett Jeffrey A , Xu Yan
Published: June 2020

Recent advances in single-cell omics and high-resolution imaging have provided unanticipated data resources for the elucidation of genes underlying the complex biological processes critical for organ formation and function. However, processing and integrating large amounts of single-cell omics and imaging data presents a major challenge for most researchers. There is a critical need for ready-to-use computational tools for data/knowledge integration and visualization. Here we present “Lung-at-a-glance”, an easy-to-use web toolset for visualizing and interoperating complex omics and imaging data, providing an interactive web interface to bridge lung anatomic ontology classifications to lung histology and immunofluorescence confocal images, and cell-type-specific gene expression. “Lung-at-a-glance” contains three interactive components: 1) “Region at a glance”, 2) “Cell at a glance” and 3) “Gene at a glance”. “Lung-at-a-glance” and other newly developed web tools for lung-related data query, integration and visualization are publicly available on LGEA web portal v3https://research.cchmc.org/pbge/lunggens/mainportal.html.
The instantaneous multi-pronged defense system of latex against general plant enemies
Authors: Salomé-Abarca Luis Francisco , Gođevac Dejan , Kim Min Sun , Hwang Geum-Sook , Park Sang Cheol , Jang Young Pyo , Cees A. M. J. J. van den Hondel , Verpoorte Robert , Klinkhamer Peter G. L. , Choi Young Hae
Published: June 2020

Based on the hypothesis that variation of the metabolomes of latex is a response to selective pressure and should thus be affected differently from other organs, their variation could provide insight into the defensive chemical selection of plants. Metabolic profiling was utilized to compare tissues ofEuphorbiaspecies collected in various regions. The metabolic variation of latexes was much more limited than that of other organs. In all of the species, the levels of polyisoprenes and terpenoids were found to be much higher in latexes than in leaves and roots. Polyisoprenes were also observed to physically delay the contact and growth of pathogens with plant tissues. A secondary barrier composed of terpenes and, in particular, 24-methylenecycloartanol, exhibited antifungal activity. These results, together with the known roles of the enzymes also present in latexes, demonstrate that they are part of a cooperative defense system that comprises both biochemical and physical elements.
Atom Identifiers Generated by a Graph Coloring Method Enable Compound Harmonization Across Metabolic Databases
Authors: Jin Huan , Mitchell Joshua M. , Moseley Hunter N.B.
Published: June 2020

Metabolic flux analysis requires both a reliable metabolic model and metabolic profiles in characterizing metabolic reprogramming. Advances in analytic methodologies enable production of high-quality metabolomics datasets capturing isotopic flux. However, useful metabolic models can be difficult to derive due to the lack of relatively complete atom-resolved metabolic networks for a variety of organisms, including human. Here, we developed a graph coloring method that creates unique identifiers for each atom in a compound facilitating construction of an atom-resolved metabolic network. What is more, this method is guaranteed to generate the same identifier for symmetric atoms, enabling automatic identification of possible additional mappings caused by molecular symmetry. Furthermore, a compound coloring identifier derived from the corresponding atom coloring identifiers can be used for compound harmonization across various metabolic network databases, which is an essential first step in network integration. With the compound coloring identifiers, 8865 correspondences between KEGG and MetaCyc compounds are detected, with 5451 of them confirmed by other identifiers provided by the two databases. In addition, we found that the Enzyme Commission numbers (EC) of reactions can be used to validate possible correspondence pairs, with 1848 unconfirmed pairs validated by commonality in reaction ECs. Moreover, we were able to detect various issues and errors with compound representation in KEGG and MetaCyc databases by compound coloring identifiers, demonstrating the usefulness of this methodology for database curation.
A harmonised systems-wide re-analysis of greenhouse gas emissions from sunflower oil production
Authors: Alcock Thomas D , Salt David E , Ramsden Stephen J
Published: June 2020

Sunflower (Helianthus annuusL.) is the largest source of vegetable oil in Europe and the fourth largest globally. Intensive cultivation and post-harvest steps contribute to global food-systems’ greenhouse gas (GHG) emissions. However, variation between production systems and reporting disparity have resulted in discordance in previous emissions estimates. To assess systems-wide GHG implications of meeting increasing edible oil demand using sunflower, we performed a unified re-analysis of primary life cycle inventory data, representing 995 farms in 11 countries, from a saturating search of published literature. Total GHG emissions varied from 1.1 to 4.2 kg CO2-equivalent per kg oil across systems, 62% of which originated from cultivation. Major emissions sources included diesel- and fertiliser-use, with irrigation electricity contributing most to between-systems variation. Our harmonised, cross-study re-analysis not only enabled robust comparisons and identification of mitigation opportunities across sunflower oil production systems, but also lays the groundwork for comparisons between alternative oil crops.
Tamoxifen reduces inflammatory infiltration of neutrophils in the airways
Authors: Mansilla Agustín , Soto Jaime , Henríquez Claudio , Philp Amber , Mall Marcus A. , Sarmiento José , Flores Carlos A.
Published: June 2020

Tamoxifen is a drug of choice for treatment of breast cancer but it has also been reported to bear anti-inflammatory activity. Previously, we have observed that tamoxifen treatment successfully reduced inflammation in horses affected by equine asthma syndrome. More notorious, tamoxifen was effective at reducing the infiltration of neutrophils in the inflamed airways by a mechanism that increases efferocytosis, allowing the resolution of inflammation. Due to the emerging increase in patients with chronic inflammatory lung diseases, there is an urgent need for therapies that help reduce airway inflammation. Thus we tested the effect of tamoxifen on airway neutrophil infiltration by using three different mouse models for acute and chronic inflammation of the lung. We found that the drug was able to produce a significant reduction in neutrophils in all scenarios. Ussing chamber experiments demonstrated that tamoxifen has no effect on fluid secretion and absorption, discarding a possible reduction in mucociliary clearance due to the known ion-channel blocking effects of tamoxifen. Since this drug has been largely used in human medicine, tamoxifen might be a “low hanging fruit” for a novel anti-inflammatory therapy for airway diseases characterized by neutrophilic inflammation.
Exploring the complexity of soybean (Glycine max) transcriptional regulation using global gene co-expression networks
Authors: Almeida-Silva Fabricio , Moharana Kanhu C. , Machado Fabricio B. , Venancio Thiago M.
Published: June 2020

Soybean (Glycine max(L.) Merr.) is one of the most important crops worldwide, constituting a major source of protein and edible oil. Gene co-expression networks (GCN) have been extensively used to study transcriptional regulation and evolution of genes and genomes. Here, we report a soybean GCN using 1,284 publicly available RNA-Seq samples from 15 distinct tissues. We found modules that are differentially regulated in specific tissues, comprising processes such as photosynthesis, gluconeogenesis, lignin metabolism, and response to biotic stress. We identified transcription factors among intramodular hubs, which probably integrate different pathways and shape the transcriptional landscape in different conditions. The top hubs for each module tend to encode proteins with critical roles, such as succinate dehydrogenase and RNA polymerase subunits. Importantly, gene essentiality was strongly correlated with degree centrality and essential hubs enriched in genes involved in nucleic acids metabolism and regulation of cell replication. By using a using a guilt-by-association approach, we predicted functions for 93 of 106 hubs without functional description in soybean. Most of the duplicated genes had different transcriptional profiles, supporting their functional divergence, although paralogs originating from whole-genome duplications (WGD) are more often preserved in the same module than those from other mechanisms. Together, our results highlight the importance of GCN analysis in unraveling key functional aspects of the soybean genome, in particular those associated with hub genes and WGD events.
Histo-morphological development of the digestive tract of larval hybrid Malaysian mahseer (Barbonymus gonionotus♀ ×Tor tambroides ♂)
Authors: Kamarudin Mohd Salleh , Ismail Muhammad Azfar , Syukri Fadhil , Latif Kamil
Published: June 2020

New carp hybrids are being developed for the aquaculture industry to support rising seafood demands. The present study was carried out to observe the changes in digestive tract, histology and functional capabilities of the new hybrid carp larvae for a better understanding of its digestive capability and the prediction of its best weaning time to a compound diet. A tubal digestive tract was elongated to the anus and buccal cavity by 3 DAH that coincided with the mouth opening and the start of exogenous feeding. A functional stomach was observed at 7 DAH with the relative gut index (RGI) of 10.7 ± 0.06. A layer of supranuclear protein was observed with lipoprotein at the outer layer of the digestive tract at 7 DAH. The morpho-histological results of this study indicated that hybrid Malaysian mahseer larvae should be able to digest, ingest and absorb an artificial diet beginning from 7 DAH. At this stage, the hybrid larvae could be gradually or perhaps totally weaned to an artificial diet of a suitable particle size.
Contribution of larvae developing on corn and dry beans to the adult population of western bean cutworm in Michigan
Authors: Bunn Dakota C. , de Oliveira Eduardo Dias , Springborn Frederick , Gonzalez-Meler Miquel A. , Miller Nicholas
Published: June 2020

The western bean cutworm,Striacosta albicosta(Smith) (Lepidoptera: Noctuidae), is historically a pest of both corn (Zea maysL.) and dry beans (Phaseolussp L.) in the western Great Plains. However, it has recently undergone an eastward range expansion establishing itself across the Corn Belt in twenty-five states and four Canadian provinces. To mitigate the effects of infestation in Michigan, foliar insecticides are used in dry beans whereas management of the pest in corn relies more heavily on the use of Bt-expressing hybrids. In this study stable carbon isotope analysis was used to determine what crop adult moths developed on as larvae with analysis showing that very few of the adult moths developed on dry beans. These results suggest that beans and corn are not suitable as co-refuges and that mainly adults which developed on corn are contributing to the next generation of western bean cutworm in Michigan.
Lineage recording reveals dynamics of cerebral organoid regionalization
Authors: He Zhisong , Gerber Tobias , Maynard Ashley , Jain Akanksha , Petri Rebecca , Santel Malgorzata , Ly Kevin , Sidow Leila , Sanchís-Calleja Fátima , Riesenberg Stephan , Camp J. Gray , Treutlein Barbara
Published: June 2020

Diverse regions develop within cerebral organoids generated from human induced pluripotent stem cells (iPSCs), however it has been a challenge to understand the lineage dynamics associated with brain regionalization. Here we establish an inducible lineage recording system that couples reporter barcodes, inducible CRISPR/Cas9 scarring, and single-cell transcriptomics to analyze lineage relationships during cerebral organoid development. We infer fate-mapped whole organoid phylogenies over a scarring time course, and reconstruct progenitor-neuron lineage trees within microdissected cerebral organoid regions. We observe increased fate restriction over time, and find that iPSC clones used to initiate organoids tend to accumulate in distinct brain regions. We use lineage-coupled spatial transcriptomics to resolve lineage locations as well as confirm clonal enrichment in distinctly patterned brain regions. Using long term 4-D light sheet microscopy to temporally track nuclei in developing cerebral organoids, we link brain region clone enrichment to positions in the neuroectoderm, followed by local proliferation with limited migration during neuroepithelial formation. Our data sheds light on how lineages are established during brain organoid regionalization, and our techniques can be adapted in any iPSC-derived cell culture system to dissect lineage alterations during perturbation or in patient-specific models of disease.
Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity
Authors: Babolmorad Ghazal , Latif Asna , Pollock Niall M. , Domingo Ivan K. , Delyea Cole , Rieger Aja M. , Allison W. Ted , Bhavsar Amit P.
Published: June 2020

Toll-like receptor 4 (TLR4) is famous for recognizing the bacterial endotoxin lipopolysaccharide (LPS) as its canonical ligand. TLR4 is also activated by other classes of agonist including some Group 9/10 transition metals. Roles for these non-canonical ligands in pathobiology mostly remain obscure, though TLR4 interactions with metals can mediate immune hypersensitivity reactions. In this work, we tested whether TLR4 can be activated by the Group 10 transition metal, platinum. We demonstrated that in the presence of TLR4, platinum activates pathways downstream of TLR4 to a similar extent as the known TLR4 agonists LPS and nickel. Platinum is the active moiety in cisplatin, a very potent and invaluable chemotherapeutic used to treat solid tumors in childhood cancer patients. Unfortunately, cisplatin use is limited due to an adverse effect of permanent hearing loss (cisplatin-induced ototoxicity, CIO). Herein, we demonstrated that cisplatin also activates TLR4, prompting the hypothesis that TLR4 mediates aspects of CIO. Cisplatin activation of TLR4 was independent of the TLR4 co-receptors CD14 and MD-2, which is consistent with TLR4 signaling elicited by transition metals. We found that TLR4 is required for cisplatin-induced inflammatory, oxidative and apoptotic responses in an ear outer hair cell line and for hair cell damagein vivo. Thus, TLR4 is a promising therapeutic target to mitigate CIO. We additionally identify a TLR4 small molecule inhibitor able to curtail cisplatin toxicityin vitro. Further work is warranted towards inhibiting TLR4 as a route to mitigating this adverse outcome of childhood cancer treatment.

Significance Statement

This work identifies platinum, and its derivative cisplatin, as new agonists for TLR4. TLR4 contributes to cisplatin-induced hair cell deathin vitroandin vivo. Genetic and small molecule inhibition of TLR4 identify this receptor as a druggable therapeutic target with promise to curtail cisplatin-induced ototoxicity, a devastating side-effect of an otherwise invaluable chemotherapeutic tool.
Learning retention mechanisms and evolutionary parameters of duplicate genes from their expression data
Authors: DeGiorgio Michael , Assis Raquel
Published: June 2020

Learning about the roles that duplicate genes play in the origins of novel phenotypes requires an understanding of how their functions evolve. To date, only one method—CDROM—has been developed with this goal in mind. In particular, CDROM employs gene expression distances as proxies for functional divergence, and then classifies the evolutionary mechanisms retaining duplicate genes from comparisons of these distances in a decision tree framework. However,CDROMdoes not account for stochastic shifts in gene expression or leverage advances in contemporary statistical learning for performing classification, nor is it capable of predicting the underlying parameters of duplicate gene evolution. Thus, here we developCLOUD, a multi-layer neural network built upon a model of gene expression evolution that can both classify duplicate gene retention mechanisms and predict their underlying evolutionary parameters. We show that not only is theCLOUDclassifier substantially more powerful and accurate thanCDROM, but that it also yields accurate parameter predictions, enabling a better understanding of the specific forces driving the evolution and long-term retention of duplicate genes. Further, application of theCLOUDclassifier and predictor to empirical data fromDrosophilarecapitulates many previous findings about gene duplication in this lineage, showing that new functions often emerge rapidly and asymmetrically in younger duplicate gene copies, and that functional divergence is driven by strong natural selection. Hence,CLOUDrepresents the best available method for classifying retention mechanisms and predicting evolutionary parameters of duplicate genes, thereby also highlighting the utility of incorporating sophisticated statistical learning techniques to address long-standing questions about evolution after gene duplication.
A mutation in theDrosophila melanogaster evestripe 2 minimal enhancer is buffered by flanking sequences
Authors: Lopez-Rivera Francheska , Foster Olivia K. , Vincent Ben J. , Pym Edward C. G. , Bragdon Meghan D. J. , Estrada Javier , DePace Angela H. , Wunderlich Zeba
Published: June 2020

Enhancers are DNA sequences composed of transcription factor binding sites that drive complex patterns of gene expression in space and time. Until recently, studying enhancers in their genomic context was technically challenging. Therefore, minimal enhancers, the shortest pieces of DNA that can drive an expression pattern that resembles a gene’s endogenous pattern, are often used to study features of enhancer function. However, evidence suggests that some enhancers require sequences outside the minimal enhancer to maintain function under environmental perturbations. We hypothesized that these additional sequences also prevent misexpression caused by a transcription factor binding site mutation within a minimal enhancer. Using theDrosophila melanogaster even-skippedstripe 2 enhancer as a case study, we tested the effect of a Giant binding site mutation (gt-2) on the expression patterns driven by minimal and extended enhancer reporter constructs. We found that, in contrast to the misexpression caused by the gt-2 binding site mutation in the minimal enhancer, the same gt-2 binding site mutation in the extended enhancer did not have an effect on expression. The buffering of expression levels, but not expression pattern, is partially explained by an additional Giant binding site outside the minimal enhancer. Mutating the gt-2 binding site in the endogenous locus had no significant effect on stripe 2 expression. Our results indicate that rules derived from mutating enhancer reporter constructs may not represent what occurs in the endogenous context.
EBSeq: improving mixing computations for multi-group differential expression analysis
Authors: Ma Xiuyu , Kendziorski Christina , Newton Michael A.
Published: June 2020

EBSeqis a Bioconductor package designed to calculate empirical-Bayesian inference summaries from sequence-based gene-expression (RNA-Seq) data. It produces gene or isoform-specific scores that measure various patterns of differential expression among a set of sample groups, and is most commonly deployed to measure differential expression between two groups. Its use of local posterior probabilities from a fitted mixture model provides the data analyst a direct way to score the false discovery rate of any reported list of genes, and it is one of the only tools that can address local false discovery rates when analyzing multiple sample groups. Contemporary applications have increasing numbers of sample groups, and the algorithms deployed inEBSeqare neither space nor time efficient in this important case. We describe a version update utilizing code improvements and novel pruning and clustering algorithms in order to reduce the complexity of mixture computations. The algorithms are supported by a theoretical analysis and tested empirically on a variety of benchmark and synthetic data sets.
FREQUENT GENE CONVERSION IN HUMAN EMBRYOS INDUCED BY DOUBLE STRAND BREAKS
Authors: Liang Dan , Gutierrez Nuria Marti , Chen Tailai , Lee Yeonmi , Park Sang-Wook , Ma Hong , Koski Amy , Ahmed Riffat , Darby Hayley , Li Ying , Dyken Crystal Van , Mikhalchenko Aleksei , Gonmanee Thanasup , Hayama Tomonari , Zhao Han , Wu Keliang , Zhang Jingye , Hou Zhenzhen , Park Jumi , Kim Chong-Jai , Gong Jianhui , Yuan Yilin , Gu Ying , Shen Yue , Olson Susan B. , Yang Hui , Battaglia David , O’Leary Thomas , Krieg Sacha A. , Lee David M. , Wu Diana H. , Duell P. Barton , Kaul Sanjiv , Kim Jin-Soo , Heitner Stephen B. , Kang Eunju , Chen Zi-Jiang , Amato Paula , Mitalipov Shoukhrat
Published: June 2020

Applications of genome editing ultimately depend on DNA repair triggered by targeted double-strand breaks (DSBs). However, repair mechanisms in human cells remain poorly understood and vary across different cell types. Here we report that DSBs selectively induced on a mutant allele in heterozygous human embryos are repaired by gene conversion using an intact wildtype homolog as a template in up to 40% of targeted embryos. We also show that targeting of homozygous loci facilitates an interplay of non-homologous end joining (NHEJ) and gene conversion and results in embryos which carry identical indel mutations on both loci. Additionally, conversion tracks may expand bidirectionally well beyond the target region leading to an extensive loss of heterozygosity (LOH). Our study demonstrates that gene conversion and NHEJ are two major DNA DSB repair mechanisms in preimplantation human embryos. While gene conversion could be applicable for gene correction, extensive LOH presents a serious safety concern.
Glyphosate used to control invasivePhragmites australisin standing water poses little risk to aquatic biota
Authors: Robichaud C.D. , Rooney R.C.
Published: June 2020

When an invasive wetland grass degrades a Ramsar wetland and Important Bird Area, decisive management action is called for. To limit the extent and spread of EuropeanPhragmites australis, the Ontario government began the first, large-scale application of glyphosate (Roundup Custom®) over standing water to control an invasive species in Canadian history. Between 2016 and 2018, over 1000 ha of marsh were treated. To assess the risk this herbicide presented to aquatic biota, we measured the concentration of glyphosate, its primary breakdown product aminomethylphosphonic acid (AMPA), and the alcohol ethoxylate-based adjuvant Aquasurf® in water and sediments in areas of the highest exposure risk and up to 150 m into adjacent bays. We never detected glyphosate or AMPA at concentrations exceeding thresholds of toxicological concern. The maximum observed concentration of glyphosate in water was 0.320 ppm, occurring within 24 hr of application. The maximum glyphosate concentration in sediment was 0.250 ppm, occurring within 30 days of application. AMPA was detectable in water and sediment, indicating microbial breakdown of glyphosate in the marsh, but at low concentrations (maxwater= 0.025 ppm, maxsed= 0.012 ppm). The maximum distance from the point of application at which glyphosate was detected in the water was 100 m, vs. 0 m for AMPA. Concentrations in water returned to pre-treatment levels (0.005 ppm) for over one year but less than two years. Concentrations of alcohol ethoxylates were variable in space and time, following a pattern that could not be attributed to Aquasurf® application. The direct, over-water application of Roundup Custom® with Aquasurf® to control invasiveP. australisdoes not pose a toxicological risk to aquatic biota.

Highlights

Glyphosate-based herbicide was applied directly to >1000 ha of marsh to control invasiveP. australis

Glyphosate and AMPA did not reach levels of toxicological concern for aquatic biota

Aquasurf® exceedances were observed but could not be attributed toP. australiscontrol activity

Glyphosate, AMPA, and Aquasurf® dispersed no more than 100 m from the point of application

Glyphosate, AMPA and Aquasurf® in water returned to baseline levels within 30 days of application

Glyphosate, AMPA and Aquasurf® in sediment returned to baseline levels within 2 years
Influenza A M2 Inhibitor Binding Understood through Mechanisms of Excess Proton Stabilization and Channel Dynamics
Authors: Watkins Laura C. , DeGrado William F. , Voth Gregory A.
Published: June 2020

Prevalent resistance to inhibitors that target the influenza A M2 proton channel has necessitated a continued drug design effort, supported by a sustained study of the mechanism of channel function and inhibition. Recent high-resolution X-ray crystal structures present the first opportunity to see how the adamantyl-amine class of inhibitors bind to M2 and disrupt and interact with the channel’s water network, providing insight into the critical properties that enable their effective inhibition in wildtype M2. In this work, we test the hypothesis that these drugs act primarily as mechanism-based inhibitors by comparing hydrated excess proton stabilization during proton transport in M2 with the interactions revealed in the crystal structures, using the Multiscale Reactive Molecular Dynamics (MS-RMD) methodology. MS-RMD, unlike classical molecular dynamics, models the hydrated proton (hydronium-like cation) as a dynamic excess charge defect and allows bonds to break and form, capturing the intricate interactions between the hydrated excess proton, protein atoms, and water. Through this, we show that the ammonium group of the inhibitors is effectively positioned to take advantage of the channel’s natural ability to stabilize an excess protonic charge and is thus acting as a hydronium-mimic. Additionally, we show that the channel is especially stable in the drug binding region, highlighting the importance of this property for binding the adamantane group. Finally, we characterize an additional hinge point near Val27, which dynamically responds to charge and inhibitor binding. Altogether, this work further illuminates a dynamic understanding of the mechanism of drug inhibition in M2, grounded in the fundamental properties that enable the channel to transport and stabilize excess protons, with critical implications for future drug design efforts.

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A novel pathway controlling cambium initiation and - activity via cytokinin biosynthesis in Arabidopsis
Authors: Rahimi Arezoo , Karami Omid , Lestari Angga Dwituti , Shi Dongbo , Greb Thomas , Offringa Remko
Published: June 2020

Plant secondary growth, also referred to as wood formation, includes the production of secondary xylem, which is derived from meristematic cambium cells embedded in vascular tissues. Despite the importance of secondary xylem in plant growth and wood formation, the molecular mechanism of secondary growth is not yet well understood. Here we identified an important role for theArabidopsis thaliana(Arabidopsis)AT-HOOK MOTIF CONTAINING NUCLEAR LOCALIZED 15 (AHL15)gene, encoding for a putative transcriptional regulator, in controlling vascular cambium activity and secondary xylem formation. Secondary xylem development was significantly reduced in inflorescence stems of the Arabidopsisahl15loss-of-function mutant, whereasAHL15overexpression led to extensive secondary xylem formation.AHL15expression under a vascular meristem-specific promoter also enhanced the amount of interfascicular secondary xylem. Moreover,AHL15appeared to be required for the enhanced secondary xylem formation in the Arabidopsis double loss-of-function mutant of theSUPPRESSOR OF OVEREXPRESSION OF CO 1(SOC1) andFRUITFULL(FUL) genes. A well-known central regulator of cambial activity is the plant hormone cytokinin. We showed that the expression of two cytokinin biosynthesis genes (ISOPENTENYL TRANSERASE (IPT) 3and7) is decreased inahl15loss-of-function mutant stems, whereas the secondary xylem deficiency in these mutant stems can be resorted by cambium-specific expression of theAgrobacterium tumefaciens IPTgene, indicating thatAHL15acts through the cytokinin pathway. These findings support a model wherebyAHL15acts as a central factor inducing vascular cambium activity downstream ofSOC1andFULand upstream ofIPT3,IPT7andLOG4, LOG5governing the rate of secondary xylem formation in Arabidopsis inflorescence stems.
Discovery of protein modifications using high resolution differential mass spectrometry proteomics
Authors: Cifani Paolo , Li Zhi , Luo Danmeng , Grivainis Mark , Intlekofer Andrew M. , Fenyö David , Kentsis Alex
Published: June 2020

Recent studies have revealed diverse amino acid, post-translational and non-canonical modifications of proteins in diverse organisms and tissues. However, their unbiased detection and analysis remain hindered by technical limitations. Here, we present a spectral alignment method for the identification of protein modifications using high-resolution mass spectrometry proteomics. Termed SAMPEI for Spectral Alignment-based Modified PEptide Identification, this open-source algorithm is designed for the discovery of functional protein and peptide signaling modifications, without prior knowledge of their identities. Using synthetic standards and controlled chemical labeling experiments, we demonstrate its high specificity and sensitivity for the discovery of sub-stoichiometric protein modifications in complex cellular extracts. SAMPEI mapping of mouse macrophage differentiation revealed diverse post-translational protein modifications, including distinct forms of cysteine itaconatylation. SAMPEI’s robust parameterization and versatility are expected to facilitate the discovery of biological modifications of diverse macromolecules. SAMPEI is implemented as a Python package, and is available open-source from BioConda and GitHub (https://github.com/FenyoLab/SAMPEI).
Does rhythmic priming improve grammatical processing in Hungarian-speaking children with and without Developmental Language Disorder?
Authors: Ladányi Enikő , Lukács Ágnes , Gervain Judit
Published: June 2020

Research has described several features shared between musical rhythm and speech or language, and experimental studies consistently show associations between performance on tasks in the two domains as well as impaired rhythm processing in children with language disorders. Motivated by these results, in the current study our first aim was to explore whether the activation of the shared system underlying rhythm and language processing with a regular musical rhythm can improve subsequent grammatical processing in preschool-aged Hungarianspeaking children with and without Developmental Language Disorder (DLD). Second, we investigated whether rhythmic priming is specific to grammar processing by assessing priming in two additional domains: a linguistic but non-grammatical task (picture naming) and a non-linguistic task (nonverbal Stroop task). Third, to confirm that the rhythmic priming effect originates from the facilitating effect of the regular rhythm and not the negative effect of the control condition, we added a third condition, silence, for all the three tasks. Both groups of children showed better performance on the grammaticality judgment task in the regular compared to both the irregular and the silent conditions but no such effect appeared in the non-grammatical and non-linguistic tasks. These results suggest that 1) rhythmic priming can improve grammatical processing in Hungarian, a language with complex morphosyntax, both in children with and without DLD, 2) the effect is specific to grammar and 3) is a result of the facilitating effect of the regular rhythm.

Research Highlights

6-year-old Hungarian-speaking children with and without Developmental Language Disorder perform better on a grammatical task subsequent to exposure to a regular rhythm vs. an irregular rhythm/silence

The effect of regular rhythm is specific: it improves performance on a grammatical task but not on a word retrieval or a non-linguistic task

Difference between performance following regular vs. irregular rhythm originates from the facilitating effect of the regular rhythm (not the negative effect of the irregular rhythm)

The results highlight the importance of rhythm in speech processing, and point towards a possible intervention tool in language disorders
Efficient and cost-effective bacterial mRNA sequencing from low input samples through ribosomal RNA depletion
Authors: Wangsanuwat Chatarin , Heom Kellie A. , Liu Estella , O’Malley Michelle A. , Dey Siddharth S.
Published: June 2020

RNA sequencing is a powerful approach to quantify the genome-wide distribution of mRNA molecules in a population to gain deeper understanding of cellular functions and phenotypes. However, unlike eukaryotic cells, mRNA sequencing of bacterial samples is more challenging due to the absence of a poly-A tail that typically enables efficient capture and enrichment of mRNA from the abundant rRNA molecules in a cell. Moreover, bacterial cells frequently contain 100-fold lower quantities of RNA compared to mammalian cells, which further complicates mRNA sequencing from non-cultivable and non-model bacterial species. To overcome these limitations, we report EMBR-seq (Enrichment of mRNA by Blocked rRNA), a method that efficiently depletes 5S, 16S and 23S rRNA using blocking primers to prevent their amplification, resulting in greater than 80% of the sequenced RNA molecules from anE. coliculture deriving from mRNA. We demonstrate that this increased efficiency provides a deeper view of the transcriptome without introducing technical amplification-induced biases. Moreover, compared to recent methods that employ a large array of oligonucleotides to deplete rRNA, EMBR-seq uses a single oligonucleotide per rRNA, thereby making this new technology significantly more cost-effective, especially when applied to varied bacterial species. Finally, compared to existing commercial kits for bacterial rRNA depletion, we show that EMBR-seq can be used to successfully quantify the transcriptome from more than 500-fold lower starting total RNA. Thus, EMBR-seq provides an efficient and cost-effective approach to quantify global gene expression profiles from low input bacterial samples.
The Impact of the Siemens Trio to Prisma Upgrade and Volumetric Navigators on MRI Indices: A Reliability Study with Implications for Longitudinal Study Designs
Authors: Plitman Eric , Bussy Aurelie , Valiquette Vanessa , Salaciak Alyssa , Patel Raihaan , Béland Marie-Lise , Tullo Stephanie , Tardif Christine , Rajah M. Natasha , Near Jamie , Devenyi Gabriel A. , Chakravarty M. Mallar
Published: June 2020

Many magnetic resonance imaging (MRI) indices are being studied longitudinally to explore topics such as biomarker detection and clinical staging. A pertinent concern to longitudinal work is MRI scanner upgrades. When upgrades occur during the course of a longitudinal MRI neuroimaging investigation, there may be an impact on the compatibility of pre- and post-upgrade measures. Similarly, subject motion is another issue that may be detrimental to longitudinal MRI work; however, embedding volumetric navigators (vNavs) within acquisition sequences has emerged as a technique that allows for prospective motion correction. Our research group recently implemented an upgrade from a Siemens MAGNETOM 3T Trio system to a Siemens MAGNETOM 3T Prisma Fit system. The goals of the current work were to: 1) investigate the impact of this upgrade on commonly used structural imaging measures and proton magnetic resonance spectroscopy indices (“Prisma Upgrade protocol”) and 2) examine structural imaging measures in a sequence with vNavs alongside a standard acquisition sequence (“vNav protocol”). In both protocols, while high reliability was observed for most of the investigated MRI outputs, suboptimal reliability was observed for certain indices. Across the scanner upgrade, increases in frontal, temporal, and cingulate cortical thickness (CT) and thalamus volume, along with decreases in parietal CT, amygdala, globus pallidus, hippocampus, and striatum volumes were observed across the Prisma upgrade, and were linked to increases in signal-to-noise ratios. No significant impact of the upgrade was found in 1H-MRS analyses. Further, CT estimates were found to be larger in MPRAGE acquisitions compared to vNav-MPRAGE acquisitions mainly within temporal areas, while the opposite was found mostly in parietal brain regions. The results from this work should be considered in longitudinal study designs and comparable prospective motion correction investigations are warranted in cases of marked head movement.
Everyone Can Meditate: Characterizing a Personalized Connectomic State Space among Meditation Groups and Non-meditators
Authors: van Doorn Jacob , Xing Mengqi , Cahn B. Rael , Delorme Arnaud , Ajilore Olusola , Leow Alex D.
Published: June 2020

Alterations in brain connectivity has been shown for many disease states and groups of people from different levels of cognitive training. To study dynamic functional connectivity, we propose a method for a personalized connectomic state space called Thought Chart. Experienced meditators are an interesting group of healthy subjects for brain connectivity analyses due to their demonstrated differences in resting state dynamics, and altered brain connectivity has been implicated as a potential factor in several psychiatric disorders. Three distinct techniques of meditation are explored: Isha Yoga, Himalayan Yoga, and Vipassana, as well as a meditation-naïve group of individuals. All individuals participated in a breath awareness task, an autobiographical thinking task, and one of three different meditation practices according to their expertise, while being recorded by a 64-electrode electroencephalogram (EEG). The functional brain connectivity was estimated using weighted phase lag index (WPLI) and the connectivity dynamics were investigated using a within-individual formulation of Thought Chart, a previously proposed dimensionality reduction method which utilizes manifold learning to map out a state space of functional connectivity. Results showed that the two meditation tasks (breath awareness task and own form of meditation) in all groups were found to have consistently different functional connectivity patterns relative to those of the instructed mind-wandering (IMW) tasks in each individual, as measured using the Hausdorff distance in the state space. The specific meditation state was found to be most similar to the breath awareness state in all groups, as expected in these meditation traditions which all incorporate breath awareness training in their practice trajectory. The difference in connectivity was found to not be solely driven by specific frequency bands. These results demonstrate that the within-individual form of Thought Chart consistently and reliably separates similar tasks among healthy meditators and non-meditators during resting state-like EEG recordings. Unexpectedly, we found the dissimilarity between breath awareness/meditation and IMW, measured via Hausdorff distance, regardless of meditation experience or tradition, with no significant group differences.
Dengue virus clinical isolates sustain viability of infected hepatic cells by counteracting apoptosis-mediated DNA breakage
Authors: Nath Himadri , Ghosh Anisa , Basu Keya , De Abhishek , Biswas Subhajit
Published: June 2020

NS1, a virotoxin, abundantly present in Dengue patients’ blood, is a major player behind disease patho-biogenesis including plasma leakage and damage to the liver. Despite the presence of NS1 in blood, Dengue is asymptomatic and self-limiting in ≥80% Dengue virus (DV) infected people. We investigated this observation and found that plasmid-mediated NS1 expression and secretion in liver cells (Huh7) are sufficient to cause programmed cell death (apoptosis) and associated cellular DNA breakage. However, liver or kidney cell lines infected with DV and secreting equivalent amounts of NS1 didn’t exhibit apoptotic DNA breakage. In fact, DV-infected cells showed better survival than cells in which only NS1 was transiently expressed by transfection. We also found that DV can even prevent chemical-induced apoptotic DNA damage in infected host cells. So, DV thwarts host antiviral defence i.e. apoptosis, by counteracting cellular DNA breakages and keeps the infected cells metabolically active to prolong virus replication.
Stress enhances hippocampal neuronal synchrony and prolongs sharp-wave ripples
Authors: Tomar Anupratap , Polygalov Denis , Chattarji Sumantra , McHugh Thomas
Published: June 2020

Chronic stress affects hippocampal function at multiple levels of neural organization. However, much of this understanding is derived from postmortem analyses of molecular, morphological, physiological and behavioral changes at fixed time points. Neural signatures of an ongoing stressful experience in the intact brain of awake animals and their links to later hippocampal dysfunction remain poorly understood. Here we usedin vivotetrode recordings to analyze the dynamic impact of 10 days of immobilization stress on neuronal activity in area CA1 of mice. Unexpectedly, there was a net decrease in pyramidal cell activity in stressed animals. Although these results suggest a lack of stress-induced hyperexcitability, more detailed analysis revealed that a greater fraction of spikes occurred specifically during sharp-wave ripples, resulting in an increase in neuronal synchrony. After repeated stress some of these alterations were visible during rest even in the absence of stress. These findings offer new insights into stress-induced alterations in ripple-spike interactions and mechanisms through which chronic stress may interfere with subsequent information processing.