bluuebunny/crossref_metadata_2025 huggingface dataset:
Leijonhufvud on New Keynesian Economics and the economics of Keynes
Authors: Trautwein Hans-Michael
Published: March 2020

The theme that Axel Leijonhufvud has extracted from the economics of Keynes is the potential for failures in the intertemporal coordination of activities in complex market systems. In his path-breaking book of 1968, he attacked standard Keynesian Economics for its view on frictions, which reduces the causes of macroeconomic pathologies to nominal rigidities. With the rise of DSGE-based New Keynesian Economics, Leijonhufvud has pointed out that ‘standard macroeconomics’ is still stuck in the frictions view. Referring to recent financial crises, he considers DSGE modelling to be hopelessly inadequate for dealing with such macroeconomic instability. Yet, the financial frictions literature in New Keynesian Economics claims to have found ways to incorporate financial crises into DSGE frameworks. The article describes continuity and change in Leijonhufvud’s critique of Old and New Keynesians, and assesses contrary claims to progress made in the DSGE world.
The First VERA Astrometry Catalog
Authors:   VERA collaboration, Hirota Tomoya , Nagayama Takumi , Honma Mareki , Adachi Yuuki , Burns Ross A , Chibueze James O , Choi Yoon Kyung , Hachisuka Kazuya , Hada Kazuhiro , Hagiwara Yoshiaki , Hamada Shota , Handa Toshihiro , Hashimoto Mao , Hirano Ken , Hirata Yushi , Ichikawa Takanori , Imai Hiroshi , Inenaga Daichi , Ishikawa Toshio , Jike Takaaki , Kameya Osamu , Kaseda Daichi , Kim Jeong Sook , Kim Jungha , Kim Mi Kyoung , Kobayashi Hideyuki , Kono Yusuke , Kurayama Tomoharu , Matsuno Masako , Morita Atsushi , Motogi Kazuhito , Murase Takeru , Nakagawa Akiharu , Nakanishi Hiroyuki , Niinuma Kotaro , Nishi Junya , Oh Chung Sik , Omodaka Toshihiro , Oyadomari Miyako , Oyama Tomoaki , Sakai Daisuke , Sakai Nobuyuki , Sawada-Satoh Satoko , Shibata Katsunori M , Shizugami Makoto , Sudo Jumpei , Sugiyama Koichiro , Sunada Kazuyoshi , Suzuki Syunsaku , Takahashi Ken , Tamura Yoshiaki , Tazaki Fumie , Ueno Yuji , Uno Yuri , Urago Riku , Wada Koji , Wu Yuan Wei , Yamashita Kazuyoshi , Yamashita Yuto , Yamauchi Aya , Yuda Akito
Published: March 2020

We present the first astrometry catalog from the Japanese VLBI (very long baseline interferometer) project VERA (VLBI Exploration of Radio Astrometry). We have compiled all the astrometry results from VERA, providing accurate trigonometric-annual-parallax and proper-motion measurements. In total, 99 maser sources are listed in the VERA catalog. Among them, 21 maser sources are newly reported, while the rest of the 78 sources are referred to in previously published results or those in preparation for forthcoming papers. The accuracy in the VERA astrometry is revisited and compared with that from the other VLBI astrometry projects such as BeSSeL (The Bar and Spiral Structure Legacy) Survey and GOBELINS (the Gould’s Belt Distances Survey) with the VLBA (Very Long Baseline Array). We have confirmed that most of the astrometry results are consistent with each other, and the largest error sources are due to source structure of the maser features and their rapid variation, along with the systematic calibration errors and different analysis methods. Combined with the BeSSeL results, we estimate the up-to-date fundamental Galactic parameters of $R_{0}=7.92\pm 0.16_{\rm {stat.}}\pm 0.3_{\rm {sys.}}\:$kpc and $\Omega _{\odot }=30.17\pm 0.27_{\rm {stat.}}\pm 0.3_{\rm {sys.}}\:$km$\:$s$^{-1}\:$kpc$^{-1}$, where $R_{0}$ and $\Omega _{\odot }$ are the distance from the Sun to the Galactic center and the Sun’s angular velocity of the Galactic circular rotation, respectively.
Molecular Genetic Risk for Psychosis Is Associated With Psychosis Risk Symptoms in a Population-Based UK Cohort: Findings From Generation Scotland
Authors: Docherty Anna R , Shabalin Andrey A , Adkins Daniel E , Mann Frank , Krueger Robert F , Bacanu Silviu-Alin , Campbell Archie , Hayward Caroline , Porteous David J , McIntosh Andrew M , Kendler Kenneth S
Published: March 2020

Objective

Subthreshold psychosis risk symptoms in the general population may be associated with molecular genetic risk for psychosis. This study sought to optimize the association of risk symptoms with genetic risk for psychosis in a large population-based cohort in the UK (N = 9104 individuals 18–65 years of age) by properly accounting for population stratification, factor structure, and sex.

Methods

The newly expanded Generation Scotland: Scottish Family Health Study includes 5391 females and 3713 males with age M [SD] = 45.2 [13] with both risk symptom data and genetic data. Subthreshold psychosis symptoms were measured using the Schizotypal Personality Questionnaire-Brief (SPQ-B) and calculation of polygenic risk for schizophrenia was based on 11 425 349 imputed common genetic variants passing quality control. Follow-up examination of other genetic risks included attention-deficit hyperactivity disorder (ADHD), autism, bipolar disorder, major depression, and neuroticism.

Results

Empirically derived symptom factor scores reflected interpersonal/negative symptoms and were positively associated with polygenic risk for schizophrenia. This signal was largely sex specific and limited to males. Across both sexes, scores were positively associated with neuroticism and major depressive disorder.

Conclusions

A data-driven phenotypic analysis enabled detection of association with genetic risk for schizophrenia in a population-based sample. Multiple polygenic risk signals and important sex differences suggest that genetic data may be useful in improving future phenotypic risk assessment.
Lineage Identification Affects Estimates of Evolutionary Mode in Marine Snails
Authors: Vaux Felix , Gemmell Michael R , Hills Simon F K , Marshall Bruce A , Beu Alan G , Crampton James S , Trewick Steven A , Morgan-Richards Mary
Published: March 2020

In order to study evolutionary pattern and process, we need to be able to accurately identify species and the evolutionary lineages from which they are derived. Determining the concordance between genetic and morphological variation of living populations, and then directly comparing extant and fossil morphological data, provides a robust approach for improving our identification of lineages through time. We investigate genetic and shell morphological variation in extant species of Penion marine snails from New Zealand, and extend this analysis into deep time using fossils. We find that genetic and morphological variation identify similar patterns and support most currently recognized extant species. However, some taxonomic over-splitting is detected due to shell size being a poor trait for species delimitation, and we identify incorrect assignment of some fossil specimens. We infer that a single evolutionary lineage (Penion sulcatus) has existed for 22 myr, with most aspects of shell shape and shell size evolving under a random walk. However, by removing samples previously classified as the extinct species P. marwicki, we instead detect morphological stasis for one axis of shell shape variation. This result demonstrates how lineage identification can change our perception of evolutionary pattern and process. [Genotyping by sequencing; geometric morphometrics; morphological evolution; Neogastropoda; phenotype; speciation; stasis.]
Molecular Mechanisms Controlling the Disease Cycle in the Vascular Pathogen Verticillium dahliae Characterized Through Forward Genetics and Transcriptomics
Authors: Sarmiento-Villamil Jorge L. , García-Pedrajas Nicolás E. , Cañizares M. Carmen , García-Pedrajas María D.
Published: March 2020

The soil-borne pathogen Verticillium dahliae has a worldwide distribution and a plethora of hosts of agronomic value. Molecular analysis of virulence processes can identify targets for disease control. In this work, we compared the global gene transcription profile of random T-DNA insertion mutant strain D-10-8F, which exhibits reduced virulence and alterations in microsclerotium formation and polar growth, with that of the wild-type strain. Three genes identified as differentially expressed were selected for functional characterization. To produce deletion mutants, we developed an updated version of one-step construction of Agrobacterium-recombination-ready plasmids (OSCAR) that included the negative selection marker HSVtk (herpes simplex virus thymidine kinase gene) to prevent ectopic integration of the deletion constructs. Deletion of VdRGS1 (VDAG_00683), encoding a regulator of G protein signaling (RGS) protein and highly upregulated in the wild type versus D-10-8F, resulted in phenotypic alterations in development and virulence that were indistinguishable from those of the random T-DNA insertion mutant. In contrast, deletion of the other two genes selected, vrg1 (VDAG_07039) and vvs1 (VDAG_01858), showed that they do not play major roles in morphogenesis or virulence in V. dahliae. Taken together the results presented here on the transcriptomic analysis and phenotypic characterization of D-10-8F and ∆VdRGS1 strains provide evidence that variations in G protein signaling control the progression of the disease cycle in V. dahliae. We propose that G protein–mediated signals induce the expression of multiple virulence factors during biotrophic growth, whereas massive production of microsclerotia at late stages of infection requires repression of G protein signaling via upregulation of VdRGS1 activity.
Identity and Pathogenicity of Fungi Associated with Crown and Root Rot of Dryland Winter Wheat in Azerbaijan
Authors: Özer Göksel , Paulitz Timothy C. , Imren Mustafa , Alkan Mehtap , Muminjanov Hafiz , Dababat Abdelfattah A.
Published: March 2020

A comprehensive survey was performed to assess fungal populations associated with crown and root rot of wheat throughout the main wheat-growing areas of Azerbaijan. Samples were taken from 76 fields; 630 fungal strains were isolated, identified, and evaluated for pathogenicity. The identification was conducted with morphological and molecular tools such as species-specific PCR and DNA sequencing of the internal transcribed spacer (ITS) and translation elongation factor 1-α (EF1-α) loci. The fungus found in the greatest number of fields (44) was Fusarium culmorum with 192 isolates, followed by F. acuminatum. Other Fusarium spp. isolates were identified: F. equiseti, F. pseudograminearum, F. graminearum, F. incarnatum, F. avenaceum, F. hostae, F. oxysporum, F. proliferatum, F. algeriense, and F. brachygibbosum. Bipolaris sorokiniana, Curvularia spicifera, Exserohilum pedicellatum, Nigrospora oryzae, and Rhizoctonia spp. isolates were also identified, associated with underground parts of wheat. Phylogenetic analyses based on ITS and EF1-α sequences of the isolates showed that the isolates belonging to the same species were clearly separated in the dendrogram. Pathogenicity assays revealed that F. culmorum, F. pseudograminearum, and F. graminearum were most aggressive; F. avenaceum, F. hostae, F. algeriense, B. sorokiniana, C. spicifera, and R. solani isolates were moderately aggressive; C. inaequalis, E. pedicellatum, and N. oryzae were weakly aggressive; and others were nonpathogenic. The result of this study exhibited the existence of a wide range of species associated with crown and root rot of wheat in Azerbaijan. Additionally, this is the first report of F. hostae, F. algeriense, C. spicifera, C. inaequalis, and N. oryzae as pathogens on wheat in Azerbaijan. Azerbaijan is the second country after Algeria in which F. algeriense was detected.
Dynamics of Population Density and Virulence Phenotype of the Soybean Cyst Nematode as Influenced by Resistance Source Sequence and Tillage
Authors: Chen Senyu
Published: March 2020

The soybean cyst nematode (SCN), Heterodera glycines, is the most damaging pathogen of soybean. Use of resistant cultivars is an effective strategy to manage SCN, but it also selects for virulent populations over time. A 12-year field experiment was initiated in 2003 to study how tillage and 11 different sequences of four cultivars impact SCN population dynamics and virulence. An SCN-susceptible cultivar and three resistant cultivars (R1, R2, and R3 derived from cultivars PI 88788, Peking, and PI 437654, respectively) were used. Tillage had minimal effect on SCN population density. Compared with no till, conventional tillage resulted in a faster increase of SCN virulence to Peking when the SCN was selected by R2 and virulence to PI 88788 by R3. Among the three SCN-resistant cultivars, R1 supported the greatest population density, R2 supported intermediate population density, and R3 supported the least SCN population density. The SCN populations selected by R1 overcame the resistance in PI 88788 but not in Peking and PI 437654. R2 selected SCN populations that overcame the resistance in Peking but not in PI 88788 and PI 437654. In contrast, R3 selected SCN populations that overcame both PI 88788 and Peking sources of resistance. There was no increase of virulence to PI 437654 in any cultivar sequence. R1 in rotation with R2 or R3 had a negative effect on female index on Peking. Susceptible soybean reduced SCN virulence to Peking, indicating that there was fitness cost of the Peking virulent SCN type. These results suggest that rotation of Peking with PI 88788 is a good strategy for managing the SCN, and susceptible cultivar and no till may reduce SCN virulence selection pressure in some rotations.

[Formula: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
North American Grape ‘Norton’ is Resistant to Grapevine Vein Clearing Virus
Authors: Qiu Wenping , Petersen Sylvia M. , Howard Susanne
Published: March 2020

Grapevines (Vitis spp.) host viruses belonging to 17 families. Virus-associated diseases are a constant challenge to grape production. Genetic resources for breeding virus-resistant grape cultivars are scarce. ‘Norton’ is a hybrid grape of North American Vitis aestivalis and is resistant to powdery mildew and downy mildew. In this study, we assessed resistance of ‘Norton’ to grapevine vein clearing virus (GVCV), which is prevalent in native, wild Vitaceae and in vineyards in the Midwest region of the U.S. We did not detect GVCV in ‘Norton’ as either the scion or the rootstock up to 3 years after it was grafted with a GVCV-infected ‘Chardonel’ grapevine. Upon sequencing of small RNAs, we were able to assemble the GVCV genome from virus small RNAs in GVCV-infected ‘Chardonel’ scion or rootstock, but not from grafted ‘Norton’ scion and rootstock. This study unveils a new trait of ‘Norton’ that can be used in breeding GVCV-resistant grape cultivars, and to investigate genetic mechanisms of ‘Norton’ resistance to GVCV.
Oxalic Acid Metabolism Contributes to Full Virulence and Pycnidial Development in the Poplar Canker Fungus Cytospora chrysosperma
Authors: Wang Yuanyuan , Wang Yonglin
Published: March 2020

Poplar Cytospora canker, which is mainly caused by Cytospora chrysosperma, is one of the most destructive and widespread tree diseases worldwide. Although oxalic acid (OA) is demonstrated as an important virulence determinant in several necrotrophic fungi, specific functions of OA during pathogenesis remain controversial. Here, we identified three genes (CcOah, CcOdc1, and CcOdc2) directly involved in OA biosynthesis and catabolism in C. chrysosperma. We demonstrated that CcOah is required for OA biogenesis. All three genes were found to be highly upregulated during early infection stages of the poplar stem. The deletion of any of the three genes led to an obvious reduction of pycnidial production but no abnormality of hyphal growth and morphology. Furthermore, the individual deletion strain exhibited significantly limited lesion sizes on poplar twigs and leaves. Exogenous application of OA or citric acid can complement the virulence defects of ΔCcOah and ΔCcOdc1 strains. We further found that the ΔCcOah strain strongly promoted reactive oxygen species burst of poplar leaves during infection. Finally, induced secretion of OA was observed by monitoring color change of the plates after poplar stem extracts were added in the cultures; however, we failed to quantify OA concentration by high-performance liquid chromatography. Taken together, the present results provide insights into the function of OA acting as an important virulence factor of C. chrysosperma.
Bacillus fungorum sp. nov., a bacterium isolated from spent mushroom substrate
Authors: Liu Xin , Wang Lingling , Han Meilin , Xue Qian-hui , Zhang Gui-shan , Gao Junlian , sun Xiaohong
Published: March 2020

A facultatively anaerobic, Gram-stain-positive, spore-forming

Bacillus

strain, 17-SMS-01T, isolated from spent mushroom substrate in the Fangshan District, Beijing, PR China, was initially identified as a

Bacillus cereus

group species based on 16S rRNA gene sequences. Strain 17-SMS-01T had the highest sequence similarities to

Bacillus wiedmannii

FSL W8-0169T (99.9 %),

Bacillus albus

N35-10-2T (99.9 %),

Bacillus luti

TD41T (99.9 %) and

Bacillus proteolyticus

TD42T (99.9 %). However, the average nucleotide identity (ANI) and digital DNA–DNA hybridization (DDH) values between strain 17-SMS-01T and the most closely related species were less than the previously proposed cut-off values of 96 % (ANI) and 70 % (DDH) for differentiating species within the genus, suggesting that this strain represents a novel

Bacillus

group species. The fatty acid profile of strain 17-SMS-01T, which showed a predominance of iso-C15 : 0 and anteiso-C15 : 0, supported the allocation of the strain to the genus

Bacillus

. The predominant menaquinone was MK-7 (100%). The major polar lipids were diphosphatidylglycerol, phosphatidyl ethanolamine, phosphatidyl glycerol, an unidentified aminophospholiped and unidentified lipids. The DNA G+C content of the novel strain was 35.0 mol%. The results of physiological and biochemical tests also allowed the phenotypic differentiation of strain 17-SMS-01T from the most closely related recognized species. On the basis of the phylogenetic and phenotypic evidence, strain 17-SMS-01T represents a novel

Bacillus

species, for which the name Bacillus fungorum sp. nov. is proposed. Type strain of the novel species is 17-SMS-01T (=MCCC 1K03483T=KCTC 33949T).
TGFβ Suppresses Type 2 Immunity to Cancer
Authors: Liu Ming , Kuo Fengshen , Capistrano Kristelle J. , Kang Davina , Nixon Briana G. , Shi Wei , Chou Chun , Do Mytrang H. , Li Shun , Stamatiades Efstathios G. , Chen Yingbei , Hsieh James J. , Hakimi A. Ari , Taniuchi Ichiro , Chan Timothy A. , Li Ming O.
Published: March 2020

The immune system employs two distinct defense strategies against infections: pathogen elimination typified by type 1 immunity, and pathogen containment exemplified by type 2 immunity in association with tissue repair. Akin to infectious diseases, cancer progresses with cancer cell acquisition of microorganism-like behavior propagating at the expense of the host. While immunological mechanisms of cancer cell elimination are well defined, whether immune-mediated cancer cell containment can be induced is poorly understood. Here we show that ablation of transforming growth factor-β receptor II (TGFβRII) in CD4+T cells promotes tumor tissue healing and halts cancer progression. Notably, the restorative response is dependent on the T helper 2 cytokine IL-4 fortifying vasculature organization that spares only proximal layers of cancer cells from hypoxia, nutrient starvation and death. Thus, type 2 immunity represents an effective cancer defense mechanism, and TGFβ signaling in helper T cells may be targeted for novel cancer immunotherapy.
Sensitive one-step isothermal detection of pathogen-derived RNAs
Authors: Woo Chang Ha , Jang Sungho , Shin Giyoung , Jung Gyoo Yeol , Lee Jeong Wook
Published: March 2020

The recent outbreaks of Ebola, Zika, MERS, and SARS-CoV-2 (2019-nCoV) require fast, simple, and sensitive onsite nucleic acid diagnostics that can be developed rapidly to prevent the spread of diseases. We have developed a SENsitive Splint-based one-step isothermal RNA detection (SENSR) method for rapid and straightforward onsite detection of pathogen RNAs with high sensitivity and specificity. SENSR consists of two simple enzymatic reactions: a ligation reaction by SplintR ligase and subsequent transcription by T7 RNA polymerase. The resulting transcript forms an RNA aptamer that induces fluorescence. Here, we demonstrate that SENSR is an effective and highly sensitive method for the detection of the current epidemic pathogen,severe acute respiratory syndrome-related coronavirus2 (SARS-CoV-2). We also show that the platform can be extended to the detection of five other pathogens. Overall, SENSR is a molecular diagnostic method that can be developed rapidly for onsite uses requiring high sensitivity, specificity, and short assaying times.
Inference and search on graph-structured spaces
Authors: Wu Charley M. , Schulz Eric , Gershman Samuel J
Published: March 2020

How do people learn functions on structured spaces? And how do they use this knowledge to guide their search for rewards in situations where the number of options is large? We study human behavior on structures with graph-correlated values and propose a Bayesian model of function learning to describe and predict their behavior. Across two experiments, one assessing function learning and one assessing the search for rewards, we find that our model captures human predictions and sampling behavior better than several alternatives, generates human-like learning curves, and also captures participants’ confidence judgements. Our results extend past models of human function learning and reward learning to more complex, graph-structured domains.
In silicoapproach toward the identification of unique peptides from viral protein infection: Application to COVID-19
Authors: Orsburn Benjamin C. , Jenkins Conor , Miller Sierra M. , Neely Benjamin A , Bumpus Namandje N
Published: March 2020

We describe a method for rapid in silico selection of diagnostic peptides from newly described viral pathogens and applied this approach to SARS-CoV-2/COVID-19. This approach is multi-tiered, beginning with compiling the theoretical protein sequences from genomic derived data. In the case of SARS-CoV-2 we begin with 496 peptides that would be produced by proteolytic digestion of the viral proteins. To eliminate peptides that would cause cross-reactivity and false positives we remove peptides from consideration that have sequence homology or similar chemical characteristics using a progressively larger database of background peptides. Using this pipeline, we can remove 47 peptides from consideration as diagnostic due to the presence of peptides derived from the human proteome. To address the complexity of the human microbiome, we describe a method to create a database of all proteins of relevant abundance in the saliva microbiome. By utilizing a protein-based approach to the microbiome we can more accurately identify peptides that will be problematic in COVID-19 studies which removes 12 peptides from consideration. To identify diagnostic peptides, another 7 peptides are flagged for removal following comparison to the proteome backgrounds of viral and bacterial pathogens of similar clinical presentation. By aligning the protein sequences of SARS-CoV-2 field isolates deposited to date we can identify peptides for removal due to their presence in highly variable regions that may lead to false negatives as the pathogen evolves. We provide maps of these regions and highlight 3 peptides that should be avoided as potential diagnostic or vaccine targets. Finally, we leverage publicly deposited proteomics data from human cells infected with SARS-CoV-2, as well as a second study with the closely related MERS-CoV to identify the two proteins of highest abundance in human infections. The resulting final list contains the 24 peptides most unique and diagnostic of SARS-CoV-2 infections. These peptides represent the best targets for the development of antibodies are clinical diagnostics. To demonstrate one application of this we model peptide fragmentation using a deep learning tool to rapidly generate targeted LCMS assays and data processing method for detecting CoVID-19 infected patient samples.

Graphical Abstract
Polysome fractionation analysis reveals features important for human nonsense-mediated mRNA decay
Authors: Lloyd James P. B. , French Courtney E. , Brenner Steven E.
Published: March 2020

Nonsense-mediated mRNA decay (NMD) is a translation-dependent mRNA surveillance pathway that eliminates transcripts with premature termination codons. Several studies have tried defined the features governing which transcripts are targeted to NMD. However, these approaches often rely on inhibiting core NMD factors, which often have roles in non-NMD processes within the cell. Based on reports that NMD-targeted transcripts are often bound by a single ribosome, we analyzed RNA-Seq data from a polysome fractionation experiment (TrlP-Seq) to characterize the features of NMD-targeted transcripts in human cells. This approach alleviates the need to inhibit the NMD pathway. We found that the exon junction complex (EJC) model, wherein an exon-exon junction located ≥50 nucleotides downstream of a stop codon is predicted to elicit NMD, was a powerful predictor of transcripts with high abundance in the monosome fraction (bound by a single ribosome). This was also true for the presence of an upstream open reading frame. In contrast, as 3’ UTR lengths increase, the proportion of transcripts that are most abundant in the monosome fraction does not increase. This suggests that either longer 3’ UTRs do not consistently act as potent triggers of NMD or that the degradation of these transcripts is mechanistically different to other NMD-targeted transcripts. Of the ribosome-associated transcripts annotated as “non-coding”, we find that a majority are bound by a single ribosome. Many of these transcripts increase in response to NMD inhibition, including the oncogenic SHNG15, suggesting many might be NMD targets. Finally, we found that retained intron transcripts without a premature termination codon are over-represented in the monosome fraction, suggesting an alternative mechanism is responsible for the low level of translation of these transcripts. In summary, our analysis finds that the EJC model is a powerful predictor of NMD-targeted transcripts, while the presence of a long 3’ UTR is not.
Positively selected modifications in the pore of TbAQP2 allow pentamidine to enterTrypanosoma brucei
Authors: Alghamdi Ali H. , Munday Jane C. , Campagnaro Gustavo D. , Gurvič Dominik , Svensson Fredrik , Okpara Chinyere E. , Kumar Arvind , Martin Abril Maria Esther , Milić Patrik , Watson Laura , Paape Daniel , Settimo Luca , Dimitriou Anna , Wielinska Joanna , Smart Graeme , Anderson Laura F. , Woodley Christopher M. , Ying Kelley Siu Pui , Ibrahim Hasan M.S. , Hulpia Fabian , Al-Salabi Mohammed I. , Eze Anthonius A. , Teka Ibrahim A. , Gudin Simon , Dardonville Christophe , Tidwell Richard R , Carrington Mark , O’Neill Paul M. , Boykin David W , Zachariae Ulrich , De Koning Harry P.
Published: March 2020

Mutations in theTrypanosoma bruceiaquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2’s unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant but exclude most other diamidine drugs. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.
Chromatin-Bound PARP1 Correlates with Upregulation of Inflammatory Genes in Response to Long-Term Treatment with Veliparib
Authors: Alvarado-Cruz Isabel , Mahmoud Mariam , Khan Mohammed , Zhao Shilin , Oeck Sebastian , Meas Rithy , Clairmont Kaylyn , Quintana Victoria , Zhu Ying , Porciuncula Angelo , Wyatt Hailey , Ma Shuangge , Shyr Yu , Kong Yong , LoRusso Patricia M. , Laverty Daniel , Nagel Zachary D. , Schalper Kurt A. , Krauthammer Michael , Sweasy Joann B.
Published: March 2020

Poly-ADP-ribose polymerase (PARP) inhibitors are active against cells and tumors with defects in homology-directed repair as a result of synthetic lethality. PARP inhibitors have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat human HCC1937BRCA1mutant and isogenicBRCA1-complemented cells for three weeks with veliparib, a PARP inhibitor. We show that long-term treatment with veliparib results in chromatin-bound PARP1 in theBRCA1mutant cells, and that this correlates with significant upregulation of inflammatory genes and activation of the cyclic GMP–AMP synthase (cGAS)/ signalling effector stimulator of interferon genes (STING) pathway. In contrast, long-term treatment of isogenicBRCA1-complemented cells with veliparib does not result in chromatin-associated PARP or significant upregulation of the inflammatory response. Our results suggest that long-term veliparib treatment may primeBRCA1mutant tumors for positive responses to immune checkpoint blockade.
Application of probioticBacillusspp. isolated from African nightcrawler (Eudrilus eugeniae) on Nile Tilapia (Oreochromis niloticusL.)
Authors: Samson J. , Quiazon K.M. , Choresca C.
Published: March 2020

Due to the emergence of antibiotic-resistant pathogens, probiotics in aquaculture are used for the prevention of infectious microbial diseases and substitute for antibiotics and chemotherapeutics. In this study, we evaluated the effect of probioticBacillusspp. isolated from African nightcrawler (Eudrilus eugeniae) on the growth, feed utilization, and disease resistance of Nile tilapia (Oreochromis niloticus). Four probiotic strains ofBacillusspp. (ANSCI9, BFAR9, RM3, and RM10) were individually incorporated in the commercial diet (control) at 108CFU g-1of feed. The experimental fish were fed at 5% of their body weight for 30 days, and subjected to a 14-dayAeromonas hydrophilachallenge test afterward. The results showed the probiotic-treated groups have higher (P<0.05) average body weight (ABW) (4.51 ± 0.34 g) than the control (3.89 ± 0.17 g). The BFAR9 (2.73 ± 0.26 g) and RM10 (3.15 ± 0.30 g) showed higher (P<0.05) absolute growth (AG) than the control (2.20 ± 0.16 g). Furthermore, RM10 had higher (P<0.05) specific growth rate (SGR) (1.60 ± 0.10 % day-1) and relative growth rate (RGR) (181.39 ± 18.16 %) than the control (SGR=1.29 ± 0.07 % day-1; RGR=129.84 ± 9.77 %). Consequently, RM10 had significantly lower (P<0.05) feed conversion ratio (FCR) (1.99 ± 0.13) than the control (2.60 ± 0.16). The challenge test revealed that the probiotic-treated groups have higher (P<0.05) survival (81.25 ± 9.57 %) than the control (55.00 ± 19.15 %). These results revealed that the probioticBacillusspp. isolated fromE. eugeniaeimproved the growth, feed utilization, and the disease resistance of Nile tilapia.
Glycine receptors are not directly modulated by glutamate, AP5 or NMDA
Authors: Aubrey Karin , Sheipouri Diba , Vandenberg Robert , Otsu Yo
Published: March 2020

3.

Reproducibility of research data is a significant problem with more than 60% of biological and medical researchers reporting they have failed to reproduce published data. General acceptance of incorrect results can mean that future data is incorrectly interpreted and progress significantly interrupted. Thus, replication studies play an essential role in corroborating research findings and validating future research objectives. Here, we attempted to replicate data demonstrating the neurotransmitter glutamate, as well as NMDA and AP5, acts as positive allosteric modulators of the inhibitory glycine receptor. Notably, it was shown that the amplitude of miniature glycinergic currents recorded in spinal cord slices were reversibly enhanced when extracellular glutamate concentrations were increased by the glutamate transporter antagonist TBOA. This finding indicates that endogenous fluctuations in extracellular [glutamate] permits cross-talk between excitatory and inhibitory synapses and likely plays a role in setting the spinal inhibitory glycinergic tone and modulating baseline neurotransmission. We re-evaluated the data in primary cultured spinal cord neurons, spinal cord slice andXenopus laevisoocytes expressing recombinant glycine receptors. Despite extensive efforts, we were unable to reproduce the finding that glutamate, AP5 or NMDA positively modulate glycine receptor currents. We paid careful attention to key aspects of the original study design, ensured rapid drug exposure by using fast-flow application and took into account receptor saturation and protocol deviations such as animal species. This study refutes the finding that glycine receptors are directly modulated by glutamate spill-over and suggests that glycinergic tone is independent of changes in excitatory activity.

4.

Significance Statement

Glutamate spill-over onto inhibitory synapses has been reported to positively modulate glycine receptors and alter the inhibitory tone of the spinal cord. This finding has important implications for baseline spinal transmission and could play a role when chronic pain develops. However, we failed to replicate these results and did not observe any modulation of native or recombinant glycine receptor-mediated currents by AP5, NMDA or glutamate. This indicates that inhibitory glycine receptors operate independently of fluctuations in extracellular [glutamate].

5.

Visual Abstract

N/A
Reshaping of theArabidopsis thalianaproteome landscape and co-regulation of proteins in development and immunity
Authors: Bassal Mona , Majovsky Petra , Thieme Domenika , Herr Tobias , Abukhalaf Mohammad , Ayash Mohamed , Al Shweiki MHD Rami , Proksch Carsten , Hmedat Ali , Ziegler Jörg , Neumann Steffan , Hoehenwarter Wolfgang
Published: March 2020

Proteome remodeling is a fundamental adaptive response and proteins in complex and functionally related proteins are often co-expressed. Using a deep sampling strategy we defineArabidopsis thalianatissue core proteomes at around 10,000 proteins per tissue and absolutely quantify (copy numbers per cell) nearly 16,000 proteins throughout the plant lifecycle. A proteome wide survey of global post translational modification revealed amino acid exchanges pointing to potential conservation of translational infidelity in eukaryotes. Correlation analysis of protein abundance uncovered potentially new tissue and age specific roles of entire signaling modules regulating transcription in photosynthesis, seed development and senescence and abscission. Among others, the data suggest a potential function of RD26 and other NAC transcription factors in seed development related to desiccation tolerance as well as a possible function of Cysteine-rich Receptor-like Kinases (CRKs) as ROS sensors in senescence. All of the components of ribosome biogenesis factor (RBF) complexes were co-expressed tissue and age specifically indicating functional promiscuity in the assembly of these little described protein complexes in Arabidopsis. Treatment of seedlings with flg22 for 16 hours allowed us to characterize proteome architecture in basal immunity in detail. The results were complemented with parallel reaction monitoring (PRM) targeted proteomics, phytohormone, amino acid and transcript measurements. We obtained strong evidence of suppression of jasmonate (JA) and JA-Ile levels by deconjugation and hydroxylation via IAA-ALA RESISTANT3 (IAR3) and JASMONATE-INDUCED OXYGENASE 2 (JOX2) under the control of JASMONATE INSENSITIVE 1 (MYC2). This previously unknown regulatory switch is another part of the puzzle of the as yet understudied role of JA in pattern triggered immunity. The extensive coverage of theArabidopsisproteome in various biological scenarios presents a rich resource to plant biologists that we make available to the community.
AnXist-dependent protein assembly mediatesXistlocalization and gene silencing
Authors: Pandya-Jones Amy , Markaki Yolanda , Serizay Jacques , Chitiashvilli Tsotne , Mancia Walter , Damianov Andrey , Chronis Costantinos , Papp Bernadett , Chen Chun-Kan , McKee Robin , Wang Xiao-Jun , Chau Anthony , Leonhardt Heinrich , Zheng Sika , Guttman Mitchell , Black Douglas L. , Plath Kathrin
Published: March 2020

Nuclear compartments play diverse roles in regulating gene expression, yet the molecular forces and components driving compartment formation are not well understood. Studying how the lncRNAXistestablishes the inactive-X-chromosome (Xi)-compartment, we found that theXistRNA-binding-proteins PTBP1, MATR3, TDP43, and CELF1 form a condensate to create an Xi-domain that can be sustained in the absence ofXist. The E-repeat-sequence ofXistserves a multivalent binding-platform for these proteins. Without the E-repeat,Xistinitially coats the X-chromosome during XCI onset but subsequently disperses across the nucleus with loss of gene silencing. Recruitment of PTBP1, MATR3, TDP-43 or CELF1 to ΔE-Xistrescues these phenotypes, and requires both self-association of MATR3 and TDP-43 and a heterotypic PTBP1-MATR3-interaction. Together, our data reveal thatXistsequesters itself within the Xi-territory and perpetuates gene silencing by seeding a protein-condensate. Our findings uncover an unanticipated mechanism for epigenetic memory and elucidate the interplay between RNA and RNA-binding-proteins in creating compartments for gene regulation.
Estimating plasmid conjugation rates: a new computational tool and a critical comparison of methods
Authors: Huisman Jana S. , Benz Fabienne , Duxbury Sarah J.N. , de Visser J. Arjan G.M. , Hall Alex R. , Fischer Egil A.J. , Bonhoeffer Sebastian
Published: March 2020

Plasmids are important vectors for the spread of genes among diverse populations of bacteria. However, there is no standard method to determine the rate at which they spread horizontally via conjugation. Here, we compare commonly used methods on simulated and experimental data, and show that the resulting conjugation rate estimates often depend strongly on the time of measurement, the initial population densities, or the initial ratio of donor to recipient populations. Differences in growth rate, e.g. induced by sub-lethal antibiotic concentrations or temperature, can also significantly bias conjugation rate estimates. We derive a new ‘end-point’ measure to estimate conjugation rates, which extends the well-known Simonsen method to include the effects of differences in population growth and conjugation rates from donors and transconjugants. We further derive analytical expressions for the parameter range in which these approximations remain valid. We present an easy to use R package and web interface which implement both new and previously existing methods to estimate conjugation rates. The result is a set of tools and guidelines for accurate and comparable measurement of plasmid conjugation rates.

Highlights

We present an R package and Shiny app to estimate conjugation rates from experimental data

We highlight the diversity of existing measures used to estimate conjugation rates

We show these measures are biased for populations with differing growth and conjugation rates from donors or transconjugants

We develop a new ‘end-point’ measure which accounts for such differences in growth and conjugation rates
SPIN reveals genome-wide landscape of nuclear compartmentalization
Authors: Wang Yuchuan , Zhang Yang , Zhang Ruochi , van Schaik Tom , Zhang Liguo , Sasaki Takayo , Hupkes Daniel Peric , Chen Yu , Gilbert David M. , van Steensel Bas , Belmont Andrew S. , Ma Jian
Published: March 2020

Chromosomes segregate differentially relative to distinct subnuclear structures, but this genome-wide compartmentalization, pivotal for modulating genome function, remains poorly understood. New genomic mapping methods can reveal chromosome positioning relative to specific nuclear structures. However, computational methods that integrate their results to identify overall intranuclear chromo-some positioning have not yet been developed. We report SPIN, a new method to identify genome-wide nuclear spatial localization patterns. As a proof-of-principle, we use SPIN to integrate nuclear compartment mapping (TSA-seq and DamID) and chromatin interaction data (Hi-C) from K562 cells to identify 10 spatial compartmentalization states genome-wide relative to nuclear speckles, lamina, and nucleoli. These SPIN states show novel patterns of genome spatial organization and their relation to genome function (transcription and replication timing). Comparisons of SPIN states with Hi-C sub-compartments and lamina-associated domains (LADs) from multiple cell types suggest constitutive compartmentalization patterns. By integrating different readouts of higher-order genome organization, SPIN provides critical insights into nuclear spatial and functional compartmentalization.
CRISPR-Csy4-mediated editing of rotavirus double-stranded RNA genome
Authors: Papa Guido , Venditti Luca , Braga Luca , Schneider Edoardo , Giacca Mauro , Petris Gianluca , Burrone Oscar R.
Published: March 2020

CRISPR-nucleases have been widely applied for editing cellular and viral genomes, but nuclease-mediated genome editing of double-stranded RNA (dsRNA) viruses has not yet been reported. Here, by engineering CRISPR-Csy4 nuclease to localise to rotavirus viral factories, we achieved the first nuclease-mediated genome editing of rotavirus, an important human and livestock pathogen with a multi-segmented dsRNA genome. Rotavirus replication intermediates cleaved by Csy4 were repaired through the formation of defined deletions in the targeted genome segments in a single replication cycle. Using CRISPR-Csy4-mediated editing of rotavirus genome, we labelled for the first time the products of rotavirus secondary transcription made by newly assembled viral particles during rotavirus replication, demonstrating that this step largely contributes to the overall production of viral proteins. We anticipate that the nuclease-mediated cleavage of dsRNA virus genomes will promote a new level of understanding of viral replication and host-pathogen interactions, offering the opportunity to develop new therapeutics.
O-GlcNAcylation of SAMHD1 Indicating a Link between Metabolic Reprogramming and Anti-HBV Immunity
Authors: Hu Jie , Gao Qingzhu , Yang Yang , Xia Jie , Zhang Wanjun , Chen Yao , Zhou Zhi , Chang Lei , Hu Yuan , Zhou Hui , Liang Li , Li Xiaosong , Long Quanxin , Wang Kai , Huang Ailong , Tang Ni
Published: March 2020

Viruses hijack the host cell machinery to promote viral replication; however, the mechanism by which metabolic reprogramming regulates innate antiviral immunity in the host remains elusive. Herein, we found that Hepatitis B virus (HBV) infection upregulates glucose transporter 1expression, promotes hexosamine biosynthesis pathway (HBP) activity, and enhances O-linked β-N-acetylglucosamine (O-GlcNAc) modification of downstream proteins. HBP-mediated O-GlcNAcylation positively regulates host antiviral response against HBVin vitroandin vivo. Mechanistically, O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) on Ser93 stabilizes SAMHD1 and enhances its antiviral activity. In addition, O-GlcNAcylation of SAMHD1 promoted its antiviral activity against human immunodeficiency virus-1in vitro. In conclusion, the results of our study reveal a link between HBP, O-GlcNAc modification, and innate antiviral immunity by targeting SAMHD1. Therefore, the results of this study demonstrate a strategy for the potential treatment of HBV infection by modulating HBP activity.
TaqMan quantitative real-time PCR for detectingAvipoxvirusDNA in various sample types from hummingbirds
Authors: Baek Hanna E. , Sehgal Ravinder N. , Bandivadekar Ruta R. , Pandit Pranav , Mah Michelle , Tell Lisa A.
Published: March 2020

Background

Avian pox is a viral disease documented in a wide range of bird species. Disease related detrimental effects can cause dyspnea and dysphagia, therefore birds with high metabolic requirements, such as hummingbirds, are especially vulnerable. Hummingbirds have a strong presence in California, especially in urban environments; however, little is understood regarding the impact of pox virus on hummingbird populations. Diagnosing pox infections relies on obtaining a tissue biopsy that poses significant bird risks and field challenges. Understanding the ecology of hummingbird pox viral infections could be advanced by a minimally invasive ante-mortem diagnostic method. This study’s goal was to address this gap in understanding if pox infections can be diagnosed using integumentary system samples besides tissue biopsies. To meet this goal, we tested multiple integumentary sample types and tested them using a quantitative real-time PCR assay. A secondary study goal was to determine which sample types (ranging from minimally to highly invasive sampling) were optimal for identifying infected birds.

Methodology/Principal Findings

Lesion tissue, pectoral muscle, feathers, toenail, blood, and swabs (both lesion tissue and non-lesion tissues) were taken from live birds and carcasses of two species of hummingbirds found in California. To maximize successful diagnosis, especially for samples with low viral load, a real-time quantitative PCR assay was developed for detecting the hummingbird-specificAvipoxvirus4b core protein gene.AvipoxvirusDNA was successfully amplified from all sample types across 27 individuals. Our results were then compared to those of conventional PCR. Comparisons were also made between sample types utilizing lesion tissue samples as the gold standard.

Conclusions/Significance

Hummingbird avian pox can be diagnosed without relying on tissue biopsies. Feather samples can be used for diagnosing infected birds and reduces sampling risk. A real-time PCR assay detected viral DNA in various integumentary system sample types and could be used for studying hummingbird disease ecology in the future.
Rhamnolipid production from waste cooking oil using newly isolated halotolerantPseudomonas aeruginosaM4
Authors: Shi Juan , Chen Yichao , Liu Xiaofeng , Ran Yi , Li Dong
Published: March 2020

This study isolated a novel halotolerantPseudomonas aeruginosaM4, that was able to degrade oil and produce rhamnolipids. Various carbon sources, nitrogen sources, inoculum ratio, pH, and temperature were tested to optimize the oil degradation conditions. The highest oil degradation rate of 85.20 % and lipase activity of 23.86 U/mL were obtained under the optimal conditions (5% inoculum at 35 °C and pH 8). The components of degradation products at different times were analyzed to explore the mechanism of oil degradation by GC-MS. Short chain fatty acid of acetic and n-butyric acids were the primary degradation intermediates.P. aeruginosaM4 had good salt tolerance up to 70 g/L. The maximum rhamnolipid concentration of 1119.87 mg/L was produced whenP. aeruginosaM4 used waste cooking oil as the sole carbon source. Rhamnose precursors were synthesized from glycerol, a hydrolysis product of waste cooking oil. R-3-hydroxyalkanoate precursors were synthesized de novo using acetyl-CoA produced from β-oxidation of fatty acids. The findings show thatP. aeruginosaM4 is a valuable biosurfactant producer in the treatment of waste cooking oil.

Key Points

P. aeruginosaisolation, oil degradation mechanism, rhamnolipid production from WCO