bluuebunny/crossref_metadata_2025 huggingface dataset:
TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration
Authors: Qiao Wei , Wong Karen H.M. , Shen Jie , Wang Wenhao , Wu Jun , Li Jinhua , Lin Zhengjie , Chen Zetao , Matinlinna Jukka P. , Zheng Yufeng , Wu Shuilin , Liu Xuanyong , Lai Keng Po , Chen Zhuofan , Lam Yun Wah , Cheung Kenneth M.C. , Yeung Kelvin W.K.
Published: April 2020

The use of magnesium ion (Mg2+)-modified biomaterials in bone regeneration is a promising and cost-effective therapeutic. Despite the widespread observation on the osteogenic effects of Mg2+, the diverse roles played by Mg2+in the complex biological process of bone healing have not been systematically dissected. Here, we reveal a previously unknown biphasic mode of action of Mg2+in bone repair. In the early inflammation phase, Mg2+primarily targets the monocyte-macrophage lineage to promote their recruitment, activation, and polarization. We showed that an increase in extracellular Mg2+contributes to an upregulated expression of transient receptor potential cation channel member 7 (TRPM7) and a TRPM7-dependent influx of Mg2+in the monocyte-macrophage lineage, resulting in the cleavage and nuclear accumulation of TRPM7-cleaved kinase fragments (M7CKs). This then triggers the phosphorylation of Histone H3 at serine 10, in a TRPM7-dependent manner at the promoters of inflammatory cytokines like IL-8, leading to the formation of a pro-osteogenic immune microenvironment. In the later active repair/remodeling phase of bone healing, however, continued exposure of Mg2+and IL-8 leads to over activation of NF-κB signaling in macrophages, turning the immune microenvironment into pro-osteoclastogenesis. Moreover, the presence of Mg2+at this stage also decelerates bone maturation through the suppression of hydroxyapatite precipitation. The negative effects of Mg2+on osteogenesis can override the initial pro-osteogenic benefits of Mg2+, as we found prolonged delivery of Mg2+compromises overall bone formation. Taken together, this study establishes a paradigm shift in understanding the diverse and multifaceted roles of Mg2+in bone healing.
Comparison of the Hi-C, GAM and SPRITE methods by use of polymer models of chromatin
Authors: Fiorillo Luca , Musella Francesco , Kempfer Rieke , Chiariello Andrea M. , Bianco Simona , Kukalev Alexander , Irastorza-Azcarate Ibai , Esposito Andrea , Conte Mattia , Prisco Antonella , Pombo Ana , Nicodemi Mario
Published: April 2020

Powerful technologies have been developed to probe chromatin 3D physical interactions genome-wide, such as Hi-C, GAM and SPRITE. Due to their intrinsic differences and without a benchmarking reference, it is currently difficult to assess how well each method represents the genome 3D structure and their relative performance. Here, we develop a computational approach to implement Hi-C, GAM and SPRITEin-silicoto compare the three methods in a simplified, yet controlled framework against known polymer 3D structures. We test our approach on models of three 6-Mb genomic regions, around theSox9and theHoxDgenes in mouse ES cells, and around theEpha4gene in mouse CHLX-12 cells. The model-derived contact matrices consistently match Hi-C, GAM and SPRITE experiments. We show thatin-silicoHi-C, GAM and SPRITE average data are overall faithful to the 3D structures of the polymer models. We find that the inherent variability of model single-molecule 3D conformations and experimental efficiency differently affect the contact data of the different methods. Similarly, the noise-to-signal levels vary with genomic distance differently inin-silicoHi-C, SPRITE and GAM. We benchmark the performance of each technology in bulk and in single-cell experiments, and identify the minimal number of cells required for replicates to return statistically consistent chromatin contact measures. Under the same experimental conditions, SPRITE requires the lowest number of cells, Hi-C is close to SPRITE, while GAM is the most reproducible method to capture interactions at large genomic distances.
Myomegalin regulates Hedgehog pathway by controlling PDE4D at the centrosome
Authors: Peng Hualing , Zhang Jingyi , Ya Amanda , Ma Winston , Villa Sammy , Sukenik Shahar , Ge Xuecai
Published: April 2020

Mutations in the Hedgehog (Hh) signaling are implicated in birth defects and cancers, including medulloblastoma, one of the most malignant pediatric brain tumors. Current Hh inhibitors face the challenge of drug resistance and tumor relapse, urging new insights in the Hh pathway regulation. Our previous study revealed how PDE4D controls global levels of cAMP in the cytoplasm to positively regulate Hh signaling; in the present study we found that a specific isoform PDE4D3 is tethered to the centrosome by myomegalin, a centrosome/Golgi associated protein. Myomegalin loss dislocates PDE4D3 from the centrosome, leading to local PKA over-activation and inhibition of the Hh signaling, leaving other PKA-related pathways unaffected. Myomegalin loss suppresses the proliferation of granule neuron precursors, and blocks the growth of medulloblastoma in mouse model. Our findings specify a new regulatory mechanism of the Hh pathway, and highlight an exciting therapeutic avenue for Hh-related cancers with reduced side effects.
Closed loop enhancement and neural decoding of human cognitive control
Authors: Basu Ishita , Yousefi Ali , Crocker Britni , Zelmann Rina , Paulk Angelique C , Peled Noam , Ellard Kristen K , Weisholtz Daniel S , Cosgrove G. Rees , Deckersbach Thilo , Eden Uri T , Eskandar Emad N , Dougherty Darin D , Cash Sydney S , Widge Alik S
Published: April 2020

Cognitive control is the ability to withhold a default, prepotent response in favor of a more adaptive choice. Control deficits are common across mental disorders, including depression, anxiety, and addiction. Thus, a method for improving cognitive control could be broadly useful in disorders with few effective treatments. Here, we demonstrate closed-loop enhancement of one aspect of cognitive control by direct brain stimulation in humans. We stimulated internal capsule/striatum in participants undergoing intracranial epilepsy monitoring as they performed a cognitive control/conflict task. Stimulation enhanced performance, with the strongest effects from dorsal capsule/striatum stimulation. We then developed a framework to detect control lapses and stimulate in response. This closed-loop approach produced larger behavioral changes than open-loop stimulation, with a slight improvement in performance change per unit of energy delivered. Finally, we decoded task performance directly from activity on a small number of electrodes, using features compatible with existing closed-loop brain implants. Our findings are proof of concept for a new approach to treating severe mental disorders, based on directly remediating underlying cognitive deficits.
DIY-NAMIC behavior: A high-throughput method to measure complex phenotypes in the homecage
Authors: Lee Jun Ho , Capan Selin , Lacefield Clay , Shea Yvonne M. , Nautiyal Katherine M.
Published: April 2020

Complex behavioral assessment is becoming increasingly necessary in order to comprehensively assessin vivomanipulations in rodent models. Using operant behavioral paradigms provides rich data sets allowing for the careful analysis of behavioral phenotypes. However, one major limitation in these studies is the expense and work-load that are required using traditional methods. The equipment for commercial operant boxes can be prohibitively expensive, and the daily experimenter effort and mouse costs required for these studies is extensive. Rodents are generally trained on task-specific paradigms for months, tested every day for 5-7 days per week. Additionally, appetitive paradigms usually require food restriction and are also commonly run in the non-active light phase of the rodent circadian rhythm. These limitations make operant behavioral testing especially difficult during adolescence, a time period of interest with regards to the development of adult-like phenotypes and a high-risk period for the development of neuropsychiatric disorders, including those which involve impulsive behavior. In order to address these issues, we developed an automated, inexpensive, open-source method which allows the implementation of most standard operant paradigms in the homecage of rodents in shorter time frames without food restriction, and with much less experimenter effort. All construction and code for the DIY Nautiyal Automated Modular Instrumental Conditioning (DIY-NAMIC) system are open source. We demonstrate their utility here by measuring impulsive behavior in a pharmacology experiment, as well as in adolescent mice.

Significance statement

Rigorous behavioral assessment is critical to understand the neural basis of neuropsychiatric disorders using animal models. Operant behavioral paradigms provide the ability to measure complex phenotypes, however, traditional methods generally require time-consuming daily training for many weeks. We designed, built, and tested an open-source automated homecage system for appetitive instrumental conditioning that enables testing in shorter timeframes with reduced experimenter effort.

Abstract Figure
Predicting the presence and titer of rabies virus neutralizing antibodies from low-volume serum samples in low-containment facilities
Authors: Meza Diana K. , Broos Alice , Becker Daniel J. , Behdenna Abdelkader , Willett Brian J. , Viana Mafalda , Streicker Daniel G.
Published: April 2020

Serology is a core component of the surveillance and management of viral zoonoses. Virus neutralization tests are a gold standard serological diagnostic, but requirements for large volumes of serum and high biosafety containment can limit widespread use. Here, focusing onRabies lyssavirus,a globally important zoonosis, we developed a pseudotype micro-neutralization rapid fluorescent focus inhibition test (pmRFFIT) that overcomes these limitations. Specifically, we adapted an existing micro-neutralization test to use a green fluorescent protein–tagged murine leukemia virus pseudotype in lieu of pathogenic rabies virus, reducing the need for specialized reagents for antigen detection and enabling use in low-containment laboratories. We further used statistical analysis to generate rapid, quantitative predictions of the probability and titer of rabies virus neutralizing antibodies from microscopic imaging of neutralization outcomes. Using 47 serum samples from domestic dogs with neutralizing antibody titers estimated using the fluorescent antibody virus neutralization test (FAVN), pmRFFIT showed moderate sensitivity (78.79%) and high specificity (84.62%). Despite small conflicts, titer predictions were correlated across tests repeated on different dates both for dog samples (r = 0.93), and for a second dataset of sera from wild common vampire bats (r = 0.72, N = 41), indicating repeatability. Our test uses a starting volume of 3.5 μL of serum, estimates titers from a single dilution of serum rather than requiring multiple dilutions and end point titration, and may be adapted to target neutralizing antibodies against alternative lyssavirus species. The pmRFFIT enables high-throughput detection of rabies virus neutralizing antibodies in low-biocontainment settings and is suited to studies in wild or captive animals where large serum volumes cannot be obtained.
Gap junctions deliver malonyl-CoA from soma to germline to support embryogenesis inCaenorhabditis elegans
Authors: Starich Todd A. , Greenstein David
Published: April 2020

Gap junctions are ubiquitous in metazoans and play critical roles in important biological processes, including electrical conduction and development. Yet, only a few defined molecules passing through gap junction channels have been linked to specific functions. We isolated gap junction channel mutants that reduce coupling between the soma and germ cells in theC. elegansgonad. We provide evidence that malonyl-CoA, the rate-limiting substrate for fatty acid synthesis (FAS), is produced in the soma and delivered through gap junctions to the germline; there it is used by fatty acid synthase to critically support embryonic development. Separation of malonyl-CoA production from its site of utilization facilitates somatic control of germline development. Additionally, we demonstrate that loss of malonyl-CoA production in the intestine negatively impacts germline development independently of FAS. Our results suggest that metabolic outsourcing of malonyl-CoA may be a strategy by which the soma communicates nutritional status to the germline.

Impact Statement

Malonyl-CoA, the rate-limiting substrate for fatty acid synthesis, is produced in the soma and delivered through gap junctions to the germline to promote reproduction and coordinate it with nutritional status.
HtsRC-mediated accumulation of F-actin regulates ring canal size during Drosophila melanogaster oogenesis
Authors: Gerdes Julianne A. , Mannix Katelynn M. , Hudson Andrew M. , Cooley Lynn
Published: April 2020

Ring canals in the female germline ofDrosophila melanogasterare supported by a robust filamentous actin (F-actin) cytoskeleton, setting them apart from ring canals in other species and tissues. Previous work has identified components required for the expansion of the ring canal actin cytoskeleton but has not identified the proteins responsible for F-actin recruitment or accumulation. Using a combination of CRISPR-Cas9 mediated mutagenesis and UAS-Gal4 overexpression, we show that HtsRC, a component specific to female germline ring canals, is both necessary and sufficient to drive F-actin accumulation. Absence of HtsRC in the germline resulted in ring canals lacking inner rim F-actin, while overexpression of HtsRC led to larger ring canals. HtsRC functions in combination with Filamin to recruit F-actin to ring-canal-like ectopic actin structures in somatic follicle cells. Finally, we present findings which indicate that HtsRC expression and robust female germline ring canal expansion are important for high fecundity in fruit flies but dispensable for their fertility, a result which is consistent with our understanding of HtsRC as a newly evolved gene specific to female germline ring canals.
Using B cell receptor lineage structures to predict affinity
Authors: Ralph Duncan K. , Matsen Frederick A.
Published: April 2020

We are frequently faced with a large collection of antibodies, and want to select those with highest affinity for their cognate antigen. When developing a first-line therapeutic for a novel pathogen, for instance, we might look for such antibodies in patients that have recovered. There exist effective experimental methods of accomplishing this, such as cell sorting and baiting; how-ever they are time consuming and expensive. Next generation sequencing of B cell receptor (BCR) repertoires offers an additional source of sequences that could be tapped if we had a reliable method of selecting those coding for the best antibodies. In this paper we introduce a method that uses evolutionary information from the family of related sequences that share a naive ancestor to predict the affinity of each resulting antibody for its antigen. When combined with information on the identity of the antigen, this method should provide a source of effective new antibodies. We also introduce a method for a related task: given an antibody of interest and its inferred ancestral lineage, which branches in the tree are likely to harbor key affinity-increasing mutations? These methods are implemented as part of continuing development of the partis BCR inference package, available athttps://github.com/psathyrella/partis.

Comments. Please post comments or questions on this paper as new issues athttps://git.io/Jvxkn.
The anti-HIV Drug Nelfinavir Mesylate (Viracept) is a Potent Inhibitor of Cell Fusion Caused by the SARS-CoV-2 Spike (S) Glycoprotein Warranting further Evaluation as an Antiviral against COVID-19 infections
Authors: Musarrat Farhana , Chouljenko Vladimir , Nabi Rafiq , Dahal Achyut , Jois Seetharama D. , Kousoulas Konstantin G.
Published: April 2020

Coronaviruses belong to a group of enveloped, positive-single stranded RNA viruses that are known to cause severe respiratory distress in animals and humans. The current SARS coronavirus-2 (SARS CoV-2) pandemic has caused more than 2,000,000 infections globally and nearly 200,000 deaths. Coronaviruses enter susceptible cells via fusion of the viral envelope with the plasma membrane and/or via fusion of the viral envelope with endosomal membranes after endocytosis of the virus into endosomes. Previous results with SARS and MERS CoV have shown that the Spike (S) glycoprotein is a major determinant of virus infectivity and immunogenicity. Herein, we show that expression of SARS CoV-2 S (S-n) glycoprotein after transient transfection of African green monkey kidney (Vero) cells caused extensive cell fusion in comparison to limited cell fusion caused by the SARS S (S-o) glycoprotein. S-n expression was detected intracellularly and on transfected Vero cell surfaces and caused the formation of very large multinucleated cells (syncytia) by 48 hours post transfection. These results are in agreement with published pathology observations of extensive syncytial formation in lung tissues of COVID-19 patients. This differential S-n versus S-o-mediated cell fusion suggests that SARS-CoV-2 is able to spread from cell-to-cell much more efficiently than SARS effectively avoiding extracellular spaces and neutralizing antibodies. A systematic screening of several drugs for ability to inhibit S-n and S-o cell fusion revealed that the FDA approved HIV-protease inhibitor, nelfinavir mesylate (Viracept) drastically inhibited S-n and S-o-mediated cell fusion in a dose-dependent manner. Complete inhibition of cell fusion was observed at a 10 micromolar concentration. Computational modeling andin silicodocking experiments suggested the possibility that nelfinavir may bind inside the S trimer structure, proximal to the S2 amino terminus directly inhibiting S-n and S-o-mediated membrane fusion. Also, it is possible that nelfinavir mesylate acts on cellular processes to inhibit S proteolytic processing. These results warrant further investigations of the potential of nelfinavir mesylate as an antiviral drug, especially at early times after SARS-CoV-2 symptoms appear.
GlobalFungi: Global database of fungal records from high-throughput-sequencing metabarcoding studies
Authors: Větrovský Tomáš , Morais Daniel , Kohout Petr , Lepinay Clémentine , Gallardo Camelia Algora , Hollá Sandra Awokunle , Bahnmann Barbara Doreen , Bílohnědá Květa , Brabcová Vendula , D’Alò Federica , Human Zander Rainier , Jomura Mayuko , Kolařík Miroslav , Kvasničková Jana , Lladó Salvador , López-Mondéjar Rubén , Martinović Tijana , Mašínová Tereza , Meszárošová Lenka , Michalčíková Lenka , Michalová Tereza , Mundra Sunil , Navrátilová Diana , Odriozola Iñaki , Piché-Choquette Sarah , Štursová Martina , Švec Karel , Tláskal Vojtěch , Urbanová Michaela , Vlk Lukáš , Voříšková Jana , Žifčáková Lucia , Baldrian Petr
Published: April 2020

Fungi are key players in vital ecosystem services, spanning carbon cycling, decomposition, symbiotic associations with cultural and wild plants and pathogenicity. The high importance of fungi in the ecosystem processes contrasts with the incompleteness of understanding of the patterns of fungal biogeography and the environmental factors that drive it. To close this gap of knowledge, we have here collected and validated data published on the composition of soil fungal communities in terrestrial environments including soil and plant-associated habitats and made them publicly accessible through a user interface athttp://globalfungi.com. The GlobalFungi database contains over 650 million observations of fungal sequences across >20 000 samples with geographical locations and additional metadata contained in 207 original studies with millions of unique sequence variants of the fungal internal transcribed spacers (ITS) 1 and 2 representing fungal species and genera. As it is, the study represents the most comprehensive atlas of fungal distribution on the global scale open to further additions.
Integrative Omics for Informed Drug Repurposing: Targeting CNS Disorders
Authors: Shukla Rammohan , Henkel Nicholas D , Alganem Khaled , Hamoud Abdul-rizaq , Reigle James , Alnafisah Rawan S , Eby Hunter M , Imami Ali S , Creeden Justin , Miruzzi Scott A , Meller Jaroslaw , Mccullumsmith Robert E.
Published: April 2020

The treatment of CNS disorders, and in particular psychiatric illnesses, lacks disease-altering therapeutics for many conditions. This is likely due to regulatory challenges involving the high cost and slow-pace of drug development for CNS disorders as well as due to limited understanding of disease causality. Repurposing drugs for new indications have lower cost and shorter development timeline compared to that of de novo drug development. Historically, empirical drug-repurposing is a standard practice in psychiatry; however, recent advances in characterizing molecules with their structural and transcriptomic signatures along with ensemble of data analysis approaches, provides informed and cost-effective repurposing strategies that ameliorate the regulatory challenges. In addition, the potential to incorporate ontological approaches along with signature-based repurposing techniques addresses the various knowledge-based challenges associated with CNS drug development. In this review we primarily discuss signature-basedin silicoapproaches to drug repurposing, and its integration with data science platforms for evidence-based drug repurposing. We contrast variousin silicoand empirical approaches and discuss possible avenues to improve the clinical relevance. These concepts provide a promising new translational avenue for developing new therapies for difficult to treat disorders, and offer the possibility of connecting drug discovery platforms and big data analytics with personalized disease signatures.
Treating Influenza and SARS-CoV-2 via mRNA-encoded Cas13a
Authors: Blanchard Emmeline L. , Vanover Daryll , Bawage Swapnil Subhash , Tiwari Pooja Munnilal , Rotolo Laura , Beyersdorf Jared , Peck Hannah E. , Bruno Nicholas C , Hincapie Robert , Finn M.G. , Michel Frank , Lafontaine Eric R. , Hogan Robert J. , Zurla Chiara , Santangelo Philip J.
Published: April 2020

Here, Cas13a has been used to target and mitigate influenza virus A (IAV) and SARS-CoV-2 using a synthetic mRNA-based platform. CRISPR RNAs (crRNA) against PB1 and highly conserved regions of PB2 were screened in conjunction with mRNA-encoded Cas13a. Screens were designed such that only guides that decreased influenza RNA levels in a Cas13-mediated fashion, were valid. Cas13a mRNA and validated guides, delivered post-infection, simulating treatment, were tested in combination and across multiplicities of infection. Their function was also characterized over time. Similar screens were performed for guides against SARS-CoV-2, yielding multiple guides that significantly impacted cytopathic effect. Last, the approach was utilizedin vivo, demonstrating the ability to degrade influenza RNA in a mouse model of infection, using polymer-formulated, nebulizer-based mRNA delivery. Our findings demonstrate the applicability of Cas13a in mitigating respiratory infections bothin vitroand in a mouse model, paving the way for future therapeutic use.
Mu Transposition in the Absence of the Target-capture Protein MuB Reveals New Roles of MuB in Target Immunity and Target Selection, and Redraws the Boundaries of the Insular Ter Region ofE. coli
Authors: Walker David M. , Harshey Rasika M.
Published: April 2020

The target capture protein MuB is responsible for the high efficiency of phage Mu transposition within theE. coligenome. However, some targets are off-limits, such as regions immediately outside the Mu ends (cis-immunity) as well as the entire ∼37 kb genome of Mu (Mu genome immunity). Paradoxically, MuB is responsible forcis-immunity and is also implicated in Mu genome immunity, but via different mechanisms. In this study, we tracked Mu transposition from six different starting locations on theE. coligenome, in the presence and absence of MuB. The data reveal that Mu’s ability to sample the entire genome during a single hop in a clonal population is independent of MuB, and that MuB is responsible forcis-immunity, plays a lesser role in Mu genome immunity, and facilitates insertions into transcriptionally active regions. Unexpectedly, transposition patterns in the absence of MuB have helped extend the boundaries of the insular Ter segment of theE. coligenome.
Chronic environmental or genetic elevation of galanin in noradrenergic neurons confers stress resilience in mice
Authors: Tillage Rachel P. , Wilson Genevieve E. , Liles L. Cameron , Holmes Philip V. , Weinshenker David
Published: April 2020

The neuropeptide galanin has been implicated in stress-related neuropsychiatric disorders in both humans and rodent models. While pharmacological treatments for these disorders are ineffective for many individuals, physical activity is beneficial for stress-related symptoms. Galanin is highly expressed in the noradrenergic system, particularly the locus coeruleus (LC), which is dysregulated in stress-related disorders and activated by exercise. Galanin expression is elevated in the LC by chronic exercise, and blockade of galanin transmission attenuates exercise-induced stress resilience. However, most research on this topic has been done in rats, so it is unclear whether the relationship between exercise and galanin is species-specific. Moreover, use of intracerebroventricular galanin receptor antagonists in prior studies precluded defining a causal role for LC-derived galanin specifically. Therefore, the goals of this study were twofold. First, we investigated whether physical activity (chronic voluntary wheel running) increases stress resilience and galanin expression in the LC of mice. Next, we used transgenic mice that overexpress galanin in noradrenergic neurons (Gal OX) to determine how chronically elevated noradrenergic-derived galanin, alone, alters anxiogenic-like responses to stress. We found that three weeks ofad libitumaccess to a running wheel in their home cage increased galanin mRNA in the LC of mice and conferred resilience to a stressor. The effects of exercise were phenocopied by galanin overexpression in noradrenergic neurons, and Gal OX mice were resistant to the anxiogenic effect of optogenetic LC activation. Together, these findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress.

Significance statement

Understanding the neurobiological mechanisms underlying behavioral responses to stress is necessary to improve treatments for stress-related neuropsychiatric disorders. Increased physical activity is associated with stress resilience in humans, but the neurobiological mechanisms underlying this effect are not clear. Here we investigate the anxiolytic potential of the neuropeptide galanin from the main noradrenergic nucleus, the locus coeruleus (LC). We show that chronic voluntary wheel running in mice galanin expression in the LC and stress resilience. Furthermore, we show that genetic overexpression of galanin in noradrenergic neurons confers resilience to the anxiogenic effects of foot shock and optogenetic LC activation. These findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress.
A Murine Model of Lyme Disease Demonstrates ThatBorrelia burgdorferiColonizes the Dura Mater and Induces Inflammation in the Central Nervous System
Authors: Casselli Timothy , Divan Ali , Tourand Yvonne , Pecoraro Heidi L. , Brissette Catherine A.
Published: April 2020

Lyme disease, which is caused by infection withBorrelia burgdorferiand related species, can lead to inflammatory pathologies affecting the joints, heart, and nervous systems including the central nervous system (CNS). Inbred laboratory mice are effective models for characterizingB. burgdorferiinfection kinetics and host immune responses in joints and heart tissues; however, similar studies are lacking in the CNS of these animals. Here we characterize the kinetics ofB. burgdorfericolonization and associated immune responses in the CNS of infected C3H mice during early and subacute infection.B. burgdorfericolonized the dura mater following needle or tick challenge, and induced expression of inflammatory cytokines and a robust IFN response as well as histopathological changes. A sterile IFN response in the absence ofB. burgdorferior inflammatory cytokines was unique to the brain parenchyma, and could provide insights into the mechanism of inflammatory CNS pathology associated with this important pathogen.
Surface chemistry-mediated modulation of adsorbed albumin folding state specifies nanocarrier clearance by distinct macrophage subsets
Authors: Vincent Michael P. , Bobbala Sharan , Karabin Nicholas B. , Frey Molly , Liu Yugang , Navidzadeh Justin O. , Stack Trevor , Scott Evan A.
Published: April 2020

Controlling nanocarrier interactions with the immune system requires a thorough understanding of the surface properties that modulate protein adsorption in biological fluids, since the resulting protein corona redefines cellular interactions with nanocarrier surfaces. Albumin is initially the dominant protein to adsorb to nanobiomaterial surfaces, a process that is considered benign or beneficial by minimizing opsonization or inflammation. Here, we demonstrate the surface chemistry of a model self-assembled nanocarrier can be engineered to stabilize or denature the three-dimensional conformation of adsorbed albumin, which respectively promotes evasion or non-specific clearancein vivo. Interestingly, certain common chemistries that have long been considered to convey stealth properties were found to promote albumin recognition by macrophage class A1 scavenger receptors (SR-A1), providing a means for their eventual removal from systemic circulation. We establish that the surface chemistry of nanocarriers can be specified to modulate adsorbed albumin structure and thereby tune clearance by macrophage scavenger receptors.
The PhoPQ two-component system is the major regulator of cell surface properties, stress responses and plant-derived substrate utilisation during development ofPectobacterium versatile-host plant pathosystem
Authors: Kravchenko Uljana , Gogoleva Natalia , Kolubako Anastasia , Kruk Alla , Diubo Julia , Gogolev Yuri , Nikolaichik Yevgeny
Published: April 2020

The PhoPQ two-component system, originally described in pectobacteria as PehRS, was previously shown to regulate a single gene,pehA. Using an insertionalphoPmutant ofPectobacterium versatile, we demonstrate that PhoP controls a regulon of at least 116 genes with a large fraction of regulon members specific for pectobacteria. The functions performed by the PhoP controlled genes include transport and metabolism of plant-derived carbon sources (polygalacturonate, arabinose and citrate), modification of bacterial cell envelope and stress resistance. High concentrations of calcium and magnesium ions were found to abolish the PhoPQ-dependent transcription activation. Reduced PhoP expression and minimisation of PhoP dependence of regulon members’ expression in the cells isolated from rotten potato tuber tissues suggest that PhoPQ system may adjust expression levels of multiple virulence-related genes during the course ofP. versatile-host plant pathosystem development.
Specialized and shared functions of diguanylate cyclases and phosphodiesterases inStreptomycesdevelopment
Authors: Haist Julian , Neumann Sara Alina , Al-Bassam Mahmoud M , Lindenberg Sandra , Elliot Marie A , Tschowri Natalia
Published: April 2020

Levels of the second messenger bis-3’-5’-cyclic di-guanosinemonophosphate (c-di-GMP) determine whenStreptomycesinitiate sporulation to survive under adverse conditions. c-di-GMP signals are integrated into the genetic differentiation network by the regulator BldD and the sigma factor σWhiG. However, functions of the development-specific c-di-GMP diguanylate cyclases (DGCs) CdgB and CdgC, and the phosphodiesterases (PDEs) RmdA and RmdB, are poorly understood. Here, we provide biochemical evidence that the GGDEF-EAL domain protein RmdB fromS. venezuelaeis a monofunctional PDE that hydrolyzes c-di-GMP to 5’pGpG. Despite having an equivalent GGDEF-EAL domain arrangement, RmdA cleaves c-di-GMP to GMP and exhibits residual DGC activity. We show that an intact EAL motif is crucial for thein vivofunction of both enzymes since strains expressing protein variants with an AAA motif instead of EAL are delayed in development, similar to null mutants. Global transcriptome analysis of ΔcdgB, ΔcdgC, ΔrmdAand ΔrmdBstrains revealed that the c-di-GMP specified by these enzymes has a global regulatory role, with about 20 % of allS. venezuelaegenes being differentially expressed in thecdgCmutant. Our data suggest that the major c-di-GMP-controlled targets determining the timing and mode of sporulation are genes involved cell division and the production of the hydrophobic sheath that coversStreptomycesaerial hyphae and spores. Altogether, this study provides a global view of the c-di-GMP-dependent genes that contribute to the hyphae-to-spores transition and sheds light on the shared and specific functions of the key enzymes involved in c-di-GMP metabolism inS. venezuelae.

Importance

Streptomycesare important producers of clinical antibiotics. The ability to synthesize these natural products is connected to their developmental biology, which includes a transition from filamentous cells to spores. The widespread bacterial second messenger c-di-GMP controls this complex switch and is a promising tool to improve antibiotic production. Here, we analyzed the enzymes that make and break c-di-GMP inS. venezuelaeby studying the genome-wide transcriptional effects of the DGCs CdgB and CdgC and the PDEs RmdA and RmdB. We found that the c-di-GMP specified by these enzymes has a global regulatory role. However, despite shared enzymatic activities, the four c-di-GMP enzymes have specialized inputs into differentiation. Altogether, we demonstrate that altering c-di-GMP levels through the action of selected enzymes yields characteristically distinct transcriptional profiles; this can be an important consideration when modulating c-di-GMP for the purposes of natural product synthesis inStreptomyces.
Sessile bacterium unlocks ability of surface motility through mutualistic interspecies interaction
Authors: Wang Miaoxiao , Geng Shuang , Hu Bing , Nie Yong , Wu Xiao-Lei
Published: April 2020

In addition to their common planktonic lifestyle, bacteria frequently live in surface-associated habitats. Surface motility is essential for exploring these habitats for food sources. However, many bacteria are found on surfaces, even though they lack features required for migrating along surfaces. How these canonical non-motile bacteria adapt to the environmental fluctuations on surfaces remains unknown. Recently, several cases of interspecies interaction were reported that induce surface motility of non-motile bacteria either by using ‘hitchhiking’ strategies or through ‘social spreading’ mechanisms. Here, we report a previously unknown mechanism for interaction-dependent surface motility of the canonical non-motile bacterium,Dietziasp. DQ12-45-1b, which is induced by interaction with a dimorphic prosthecate bacterium,Glycocaulis alkaliphilus6B-8T.Dietziacells exhibits “sliding”-like motility in an area where the strainGlycocauliscells was pre-colonized with a sufficient density. Furthermore, we show that biosurfactants play a critical role in inducing the surface motility ofDietziacells. Our analysis also demonstrates thatDietziadegrade n-alkanes and provideGlycocauliswith the resulting metabolites for survival, which in turn enabled directional migration ofDietziatowards nutrients in the environment. Such interaction-dependent migration was also found betweenDietziaandGlycocaulisstrains isolated from other habitats, suggesting that this mutualistic relationship ubiquitously occurs in natural environments. In conclusion, we propose a novel model for such a ‘win-win’ strategy, whereby non-motile bacteria pay metabolites to dimorphic prosthecate bacteria in return for migrating to reach environments otherwise inaccessible. We propose that this mechanism represents a common strategy for canonically non-motile bacteria living on a surface.

Importance

Cell motility provides a selective advantage for bacteria searching for nutrients. While a large body of evidence exists for how motile bacteria migrate on surface by virtue of different ways of motility, fewer studies concerned about how canonical non-motile bacteria adapted to those surface-associated habitats. Recent reports have proposed that interactions with other bacteria trigger the movement of those sessile bacteria. However, these interactions are limited to ‘hitchhiking’ or ‘social spreading’ modes. Here, we characterized a previously unknown interaction mode betweenDietziaandGlycocaulis.

This interaction differs from previously described modes, thus advance our limited understanding of how sessile bacteria move on surfaces. We propose that this interaction mode represents a ‘win-win’ strategy for both strains, and this mode might be widely distributed across diverse environments. These novel insights should greatly assist in understanding the mechanisms responsible for the cellular interplay between microbes in complex microbiomes.
Geographic and subsequent biotic isolations led to a diversity anomaly ofHeterotropa(Aristolochiaceae) in insular versus continental regions of the Sino-Japanese Floristic Region
Authors: Takahashi Daiki , Feng Yu , Sakaguchi Shota , Isagi Yuji , Qiu Ying-Xiong , Li Pan , Lu Rui-Sen , Lu Chang-Tse , Chung Shih-Wen , Lin Yang-Shan , Chen Yun-Chao , Nagano Atsushi J. , Kawaguchi Lina , Setoguchi Hiroaki
Published: April 2020

The Sino-Japanese Floristic Region is highly diverse with respect to temperate plants. However, the reasons for this diversity are poorly understood because most studies have only considered geographic isolation caused by climatic oscillations.Heterotropa(genusAsarum; Aristolochiaceae) diverges here and shows high species diversity in insular systems (63 species) compared to continental areas (25 species).Heterotropashows low dispersal ability with small distribution ranges, implying diversification by geographic events, and high floral diversity, implying pollinator-mediated diversification. To reveal how abiotic and biotic factors have shaped the diversity anomaly ofHeterotropa, we conducted phylogenetic analysis using ddRAD-seq and chloroplast genome datasets including 79 species, estimation of floral trait evolution, and comparison of isolation factors within clades based on distribution range and floral trait analysis. Phylogenetic analysis indicates thatHeterotropaoriginated in mainland China and expanded to the Japanese Archipelago in the Miocene, and the major clades almost correspond to geographic distributions. Floral traits evolved repeatedly in the tip nodes within the clades. Although the major clades include a high proportion of species pairs showing isolation by floral traits, there are no conditional relationships between two isolation factors, indicating that most species pairs with floral trait isolation are distributed allopatrically. The repeated exposure and submergence of land-bridges caused by climatic oscillations would have led to significant population fragmentation in insular systems. Thus, the diversity anomaly ofHeterotropawould have resulted from geographic and climatic events during the Miocene, while subsequent repeated floral trait evolution would have followed geographic isolation during the Pleistocene.
Convergence in per capita CO2emissions: evidence from nonlinear unit root tests in top four oil exporter countries
Authors: Saliminezhad Andisheh , Bahramian Pejman
Published: April 2020

Purpose

This paper aims to examine the stochastic convergence of the per capita CO2emissions among the top four crude oil exporter countries, namely, Canada, Iraq, Russia and Saudi Arabia, from 1960 to 2017. Assessing the stationarity and unit root properties of the environmental series in these countries is important as their large fossil fuel resources increases the potential for rising CO2emissions compared to other countries.

Design/methodology/approach

In addition to implementing the conventional unit root tests, the authors also benefit from the application of three nonlinear unit root tests, namely, wavelet unit root test, nonlinear unit root test of Güriş (2019) and the Fourier quantile unit root test. These methods are robust to the presence of possible structural breaks and other forms of nonlinearities, while the wavelet unit root test enables us to examine the stochastic behavior of the variables in both time and frequency domains. Hence, they all provide more reliable inferences on the convergences of the CO2emissions compared to their standard competitors.

Findings

The standard unit root test results show strong evidence in favor of non-stationarity in all countries. This conclusion supports the results of the other nonlinear unit root tests and the overall findings of the Fourier quantile unit root test. The wavelet unit root test provides a controversial finding. However, due to its limitations, its findings must be interpreted with caution. The details of the Fourier quantile unit root test indicate that per capita CO2emissions follow mean-reverting properties in middle quantile ranges for Canada, Russia and Iraq. This validates the asymmetric behaviors of per capita CO2emissions in these countries.

Originality/value

The novelty of the work can be stated in two ways. First, among the available studies, this is the first paper to emphasize the importance of examining the convergence of per capita CO2emissions among the top four oil exporters. Second, to the best of the knowledge, no study has yet been undertaken in which all these methods have been simultaneously applied. Sustainable environmental policies depend heavily on the CO2series’ properties. Thus, the findings can provide significant environmental and economic implications for policymakers to construct feasible and optimal policies in climate change mitigation.
Betting on capital gains: housing speculation in Auckland, New Zealand
Authors: Rehm Michael , Yang Yang
Published: April 2020

Purpose

The purpose of this paper is to examine housing speculation in Auckland, New Zealand, the second most unaffordable market in the world.

Design/methodology/approach

The study considers rental property purchases from 2002 to 2016 within the Auckland region. The authors apply a simple cash flow model that emulates the before-tax investment calculations used during purchasers’ due diligence. From this model, the authors determine whether purchases involved speculation on capital gains or not and the authors estimate the degree of speculation at the transaction level.

Findings

The authors find that housing speculation in Auckland is endemic and its housing market is a politically condoned, finance-fuelled casino with investors broadly betting on tax-free capital gains.

Social implications

Although political leaders have decried that the “speculation-driven housing bubble in Auckland is a social and economic disaster”, the government’s main anti-speculation tool – the Income Tax Act’s intention test – sits idle and inoperable. By holstering this key policy tool, politicians foster housing speculation and use residential property investment to buttress New Zealand’s asset-based welfare system.

Originality/value

The authors develop novel methods to objectively distinguish speculators from genuine investors, measure the speculative pressure applied by individual rental property purchasers and outline an evidence-based approach to operationalise New Zealand’s currently impotent anti-speculation tool, the intention test.
Does accounting details play an allocative role in predicting macroeconomic indicators? Evidence of Bayesian and classical econometrics in Iran
Authors: Salehi Mahdi , Daemi Gah Ali , Akbari Farzana , Naghshbandi Nader
Published: April 2020

Purpose

The purpose of this study is to analyze the predictability of firm level data for determining macroeconomic indicators such as unemployment.

Design/methodology/approach

This study uses quarterly GDP and unemployment data manually collected from the Statistical Center of Iran (SCI). Accounting numbers are also collected from the Tehran Stock Exchange library for the 2004-2015 period. Dispersion of earnings growth provides related data about labour reallocation, unemployment change and finally aggregate output. To summarize, this study attempts to examine the effect of these variables using classical and Bayesian approaches.

Findings

At a firm level, our results suggest that sectoral shift in previous years is likely to increase labour reallocation in subsequent years. At the macro level, the results reveal that dispersion of earnings growth and labour reallocation has a negative and positive impact on unemployment changes, respectively. However, the study suggests no significant relationship between stock return and unemployment changes. Consequently, we determine that the real estimates of macroeconomic indicators have predictive power because nominal estimates are not statistically associated with firm-level details. Finally, the results obtained from classical and Bayesian approaches suggest similar findings, thus confirming the robustness of our conclusions. Note that, based on Bayesian approach, the nominal reallocation has predictive power in unemployment rate.

Originality/value

The study is the first conducted in a developing country and the results provide important insight into current line of accounting literature.
Innovation management practices: analysis of small family farmers on the border of Brazil and Paraguay
Authors: Diaz-Villavicencio Guillermo
Published: April 2020

Purpose

This paper aims to focus on the innovation practices of small family businesses (rural farmers) living in border areas. Previous studies on small rural businesses have a low level of knowledge of innovation practices. The author acknowledges that technological innovation affects small farmers and it has a positive impact on the company’s performance. The proposal is to analyze the contribution of innovation practices in a group of small rural farmers that have similar characteristics in border countries. The potential for innovation management in the border business is also discussed.

Design/methodology/approach

The hypothesis was approved with a sample of 71 small family farms and using a multiple linear regression model. This study examines those pointed 40 innovation management practices, on the border of Brazil and Paraguay in 2018. The practices were divided into five constructs, namely, strategy, processes, organisation, linkages and learning and was measured via the Likert Scale (1932) in which 1 is “not true at all” and 7 is “very true”.

Findings

The results show that small family farms are far from displaying constant management practices in innovation, as such, the author gives general recommendations for the small companies of this study.

Research limitations/implications

The study relies on self-reported data and it does not have a longitudinal design.

Practical implications

An important implication of this research study is that small rural organisations can become aware of the importance of generating innovation practices to achieve better long-term performance.

Social implications

Knowing whether border family farms are or have components of innovation management is a relevant issue for the generation of public policies aimed at improving the agricultural sector in the area. Borders often do not allow us to see the neighbors and the author ends up generating pre-concepts about all kinds of actions. However, the author sees in this study that there are common variables to develop a public policy of frontiers oriented to family farms.

Originality/value

The study innovates by including the same variables in the model (survey for both countries) and which can contribute to generating innovation practices in small border agricultural companies, where, clearly, the international norms and laws of each country influence each productive unit differently.