bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural basis of reiterative transcription from the pyrG and pyrBI promoters by bacterial RNA polymerase
Authors: Shin Yeonoh , Hedglin Mark , Murakami Katsuhiko S
Published: January 2020

Reiterative transcription is a non-canonical form of RNA synthesis by RNA polymerase in which a ribonucleotide specified by a single base in the DNA template is repetitively added to the nascent RNA transcript. We previously determined the X-ray crystal structure of the bacterial RNA polymerase engaged in reiterative transcription from the pyrG promoter, which contains eight poly-G RNA bases synthesized using three C bases in the DNA as a template and extends RNA without displacement of the promoter recognition σ factor from the core enzyme. In this study, we determined a series of transcript initiation complex structures from the pyrG promoter using soak–trigger–freeze X-ray crystallography. We also performed biochemical assays to monitor template DNA translocation during RNA synthesis from the pyrG promoter and in vitro transcription assays to determine the length of poly-G RNA from the pyrG promoter variants. Our study revealed how RNA slips on template DNA and how RNA polymerase and template DNA determine length of reiterative RNA product. Lastly, we determined a structure of a transcript initiation complex at the pyrBI promoter and proposed an alternative mechanism of RNA slippage and extension requiring the σ dissociation from the core enzyme.
DNA storage: research landscape and future prospects
Authors: Dong Yiming , Sun Fajia , Ping Zhi , Ouyang Qi , Qian Long
Published: January 2020

The global demand for data storage is currently outpacing the world's storage capabilities. DNA, the carrier of natural genetic information, offers a stable, resource- and energy-efficient and sustainable data storage solution. In this review, we summarize the fundamental theory, research history, and technical challenges of DNA storage. From a quantitative perspective, we evaluate the prospect of DNA, and organic polymers in general, as a novel class of data storage medium.
Cigarette Smoking and Nicotine Dependence Trajectories Among Incident Adolescent Smokers
Authors: Mésidor Miceline , Sylvestre Marie-Pierre , Minoyan Nanor , O’Loughlin Jennifer
Published: January 2020

Introduction

Few interventions target adolescent cigarette smokers to prevent escalation in cigarette use or promote cessation, in part because little is known about co-developing smoking and nicotine dependence (ND). Our objectives were to: (1) estimate developmental trajectories of ND/cravings, withdrawal symptoms, the modified Fagerström Tolerance Questionnaire (mFTQ) and ICD-10 tobacco dependence in incident adolescent smokers; (2) describe concordance in number and shapes of trajectories across the four ND indicators; and (3) classify participants in each ND trajectory according to cigarette smoking trajectories.

Methods

Data were drawn from an ongoing longitudinal investigation of 1294 grade 7 students recruited in 1999–2000 in 10 Montreal-area high schools. Group-based joint trajectory models were used to identify distinct subgroups defined by the four ND indicators, in 307 incident smokers.

Results

The optimal trajectory model included five groups for ND/craving and four groups for each of withdrawal symptoms, the mFTQ and ICD-10 tobacco dependence. The four ND indicators showed similar developmental patterns and classification into smoking trajectory groups, although some discordance was observed. Smokers in the low-level decreaser group and stable low consumers who exhibited high ND were younger than those in the cigarette-low ND trajectory groups. Moderate or rapid escalators who exhibited no/low ND were less likely to have university-educated mothers and more likely to have parents who smoke.

Conclusions

Trajectories were similar across ND indicators, and generally reflected cigarette smoking trajectory shapes. Novice smokers may need education to become self-aware of developing ND symptoms, as well as to learn about alternative courses of action once ND symptoms manifest.

Implications

Trajectories of cigarette smoking and ND symptoms have rarely been investigated concurrently. This study provides evidence of high concordance across four distinct ND indicators in the proportion of participants with no/low-level dependence, and with high or increasing ND. Moreover, the development of cigarette smoking is concordant with ND symptom development. Interventions to prevent escalation and promote cessation should target adolescents before first puff to increase self-awareness of developing ND symptoms, as well as to learn about alternative courses of action once ND symptoms are experienced.
Regulatory Certification, Risk Factor Disclosure, and Investor Behavior
Authors: Cox Ruben , de Goeij Peter
Published: January 2020

This article examines the question: Does regulatory approval of prospectuses act as a “certification” of securities offerings? Rational investors should generally ignore prospectus approval due to its being uninformative regarding either the quality of, or motives for, the underlying offering. Our survey experiment demonstrates that salient references to regulatory oversight in investment advertisements can lead to significant increases in willingness to invest and concomitant decreases in perceived risks. Conversely, salient disclosure of risk factor information increases risk perceptions and reduces the intention to search for additional information. Various robustness tests confirm that investors can perceive regulatory oversight of securities offerings as an endorsement. Our results provide insight regarding the design of the disclosure and the effective regulation of financial marketing.
The effect of sleep duration on hemoglobin and hematocrit: observational and Mendelian randomization study
Authors: Wang Jiao , Kwok Man Ki , Au Yeung Shiu Lun , Li Albert Martin , Lam Simon , Leung Gabriel Matthew , Schooling Catherine Mary
Published: January 2020

Study Objective

Observationally sleep duration is positively associated with hemoglobin (Hgb), whether this association is causal and consistent by sex remains unclear. Here, we assessed the association of sleep duration with Hgb and hematocrit (Hct) observationally in late adolescence in a population-representative Chinese birth cohort “Children of 1997” with validation using Mendelian randomization (MR) in adults.

Methods

In the “Children of 1997” birth cohort (recruited = 8327, included = 3144), we used multivariable linear regression to assess the adjusted associations of sleep duration (measured as time in bed) with Hgb and Hct at 17.5 years and any sex differences. Using two-sample MR, we assessed the effect of sleep duration on Hgb and Hct, based on 61 single nucleotide polymorphisms (SNPs) applied to genome-wide association studies of Hgb and Hct in adults (n = 361 194).

Results

Observationally, self-reported sleep duration was positively associated with Hct (0.034 standard deviations [SDs] per hour, 95% confidence interval [CI] 0.019 to 0.049), but not with Hgb. Using MR longer sleep increased Hct (0.077 SD per hour, 95% CI 0.035 to 0.119) and Hgb (0.065 SD per hour, 95% CI 0.020 to 0.109) using Mendelian randomization pleiotropy residual sum and outlier (MR PRESSO), with more pronounced associations in men.

Conclusions

Our novel findings indicate sleep increases both Hgb and Hct, particularly in men, perhaps contributing to its restorative qualities. Potential difference by sex and the implications of these findings warrant investigation.
Estimating Phylogenies from Shape and Similar Multidimensional Data: Why It Is Not Reliable
Authors: Varón-González Ceferino , Whelan Simon , Klingenberg Christian Peter
Published: January 2020

In recent years, there has been controversy whether multidimensional data such as geometric morphometric data or information on gene expression can be used for estimating phylogenies. This study uses simulations of evolution in multidimensional phenotype spaces to address this question and to identify specific factors that are important for answering it. Most of the simulations use phylogenies with four taxa, so that there are just three possible unrooted trees and the effect of different combinations of branch lengths can be studied systematically. In a comparison of methods, squared-change parsimony performed similarly well as maximum likelihood, and both methods outperformed Wagner and Euclidean parsimony, neighbor-joining and UPGMA. Under an evolutionary model of isotropic Brownian motion, phylogeny can be estimated reliably if dimensionality is high, even with relatively unfavorable combinations of branch lengths. By contrast, if there is phenotypic integration such that most variation is concentrated in one or a few dimensions, the reliability of phylogenetic estimates is severely reduced. Evolutionary models with stabilizing selection also produce highly unreliable estimates, which are little better than picking a phylogenetic tree at random. To examine how these results apply to phylogenies with more than four taxa, we conducted further simulations with up to eight taxa, which indicated that the effects of dimensionality and phenotypic integration extend to more than four taxa, and that convergence among internal nodes may produce additional complications specifically for greater numbers of taxa. Overall, the simulations suggest that multidimensional data, under evolutionary models that are plausible for biological data, do not produce reliable estimates of phylogeny. [Brownian motion; gene expression data; geometric morphometrics; morphological integration; squared-change parsimony; phylogeny; shape; stabilizing selection.]
Persistence of symptoms in dengue patients: a clinical cohort study
Authors: Tiga-Loza Diana Carolina , Martínez-Vega Ruth A , Undurraga Eduardo A , Tschampl Cynthia A , Shepard Donald S , Ramos-Castañeda José
Published: January 2020

Background

Dengue is commonly considered an acute illness and follows three phases: febrile, critical in some cases and recovery. However, a number of studies have described a continuation of dengue symptoms for weeks or months, extending the recovery phase. Here we evaluate this persistence of dengue symptoms during convalescence.

Methods

Our clinical cohort study included patients who sought medical services 48 to 144 h from the onset of fever at seven hospitals or ambulatory centers in Morelos, Mexico. Seventy-nine laboratory-confirmed dengue patients were followed up regularly using clinic and/or home visits and telephone calls for as long as symptoms persisted or up to 6 mo.

Results

In total, 55.7% of patients had dengue-related symptoms 1 mo after the onset of fever; pain and dermatological manifestations were the most common persistent symptoms. Prognostic factors for symptom persistence were: ≥4 d of fever (RR 1.72; 95% CI 1.35 to 2.19), platelet count ≤100 000/mm3 (RR 1.20; 95% CI 1.20 to 2.20), petechiae/bruises (RR 1.97; 95% CI 1.56 to 2.48) and abdominal pain/hepatomegaly (RR 1.79; 95% CI 1.41 to 2.28).

Conclusions

Persistence of dengue symptoms were common in laboratory-confirmed dengue patients. Manifestations related to tissue damage were associated with persistence after 30 d; host characteristics, such as age and health status before infection, were associated with prolonged persistence (>60 d). The burden of dengue may be higher than previously estimated.
Genome Sequences of Verticillium dahliae Defoliating Strain XJ592 and Nondefoliating Strain XJ511
Authors: Li Haiyuan , Dai Jichen , Qin Jun , Shang Wenjing , Chen Jieyin , Zhang Li , Dai Xiaofeng , Klosterman Steven J. , Xu Xiangming , Subbarao Krishna V. , Fan Sanhong , Hu Xiaoping
Published: January 2020

Verticillium dahliae is a widely distributed soilborne pathogen that causes vascular wilt in more than 200 plant species. Defoliating and nondefoliating symptoms caused by the disease that result in either the loss or retention of leaves in infected plants, respectively, in hosts such as cotton, olive, and okra, divide the causal agent into defoliating and nondefoliating pathotypes. Our goal in this current work was to generate genome resources for the defoliating strain XJ592 and the nondefoliating strain XJ511 of V. dahliae isolated from cotton in China.
Metformin-Associated Lactic Acidosis
Authors: Hevesy Martin R.
Published: January 2020

Many Type 2 diabetic patients take metformin for its safety profile and lack of hypoglycemia. Although this drug is safe in those without renal dysfunction, lactic acidosis may rarely occur. Metformin-associated lactic acidosis is a potentially fatal yet rare diagnosis. Prompt recognition of even subtle symptoms can reduce mortality and preserve homeostasis.
Exascale applications: skin in the game
Authors: Alexander Francis , Almgren Ann , Bell John , Bhattacharjee Amitava , Chen Jacqueline , Colella Phil , Daniel David , DeSlippe Jack , Diachin Lori , Draeger Erik , Dubey Anshu , Dunning Thom , Evans Thomas , Foster Ian , Francois Marianne , Germann Tim , Gordon Mark , Habib Salman , Halappanavar Mahantesh , Hamilton Steven , Hart William , (Henry) Huang Zhenyu , Hungerford Aimee , Kasen Daniel , Kent Paul R. C. , Kolev Tzanio , Kothe Douglas B. , Kronfeld Andreas , Luo Ye , Mackenzie Paul , McCallen David , Messer Bronson , Mniszewski Sue , Oehmen Chris , Perazzo Amedeo , Perez Danny , Richards David , Rider William J. , Rieben Rob , Roche Kenneth , Siegel Andrew , Sprague Michael , Steefel Carl , Stevens Rick , Syamlal Madhava , Taylor Mark , Turner John , Vay Jean-Luc , Voter Artur F. , Windus Theresa L. , Yelick Katherine
Published: January 2020

As noted in Wikipedia,skin in the gamerefers to having ‘incurred risk by being involved in achieving a goal’, where ‘skinis a synecdoche for the person involved, andgameis the metaphor for actions on the field of play under discussion’. For exascale applications under development in the US Department of Energy Exascale Computing Project, nothing could be more apt, with theskinbeing exascale applications and thegamebeing delivering comprehensive science-based computational applications that effectively exploit exascale high-performance computing technologies to provide breakthrough modelling and simulation and data science solutions. These solutions will yield high-confidence insights and answers to the most critical problems and challenges for the USA in scientific discovery, national security, energy assurance, economic competitiveness and advanced healthcare.

This article is part of a discussion meeting issue ‘Numerical algorithms for high-performance computational science’.
Insight into the resistome and quorum sensing system of a divergent Acinetobacter pittii isolate from an untouched site of the Lechuguilla Cave
Authors: Gan Han Ming , Wengert Peter , Barton Hazel A. , Hudson André O , Savka Michael A.
Published: January 2020

Acinetobacter

are Gram-negative bacteria belonging to the sub-phyla

Gammaproteobacteria

, commonly associated with soils, animal feeds and water. Some members of the

Acinetobacter

have been implicated in hospital-acquired infections, with broad-spectrum antibiotic resistance. Here we report the whole-genome sequence of LC510, an

Acinetobacter

species isolated from deep within a pristine location of the Lechuguilla Cave. Pairwise nucleotide comparison to three type strains within the genus

Acinetobacter

assigned LC510 as an

Acinetobacter pittii

isolate. Scanning of the LC510 genome identified two genes coding for b-lactamase resistance, despite the fact that LC510 was isolated from a portion of the cave not previously visited by humans and protected from anthropogenic input. The ability to produce acyl-homoserine lactone (AHL) signal in culture medium, an observation that is consistent with the identification of the luxI and luxR homologues in its genome, suggests that cell-to-cell communication remains important in an isolated cave ecosystem.
Ceftolozane–tazobactam- and ceftazidime–avibactam-resistant Pseudomonas aeruginosa mastoiditis
Authors: Jacobs Jeremy , Maris Alexander , Stratton Charles
Published: January 2020

Pseudomonas aeruginosa is an important bacterial cause of a variety of infections and is associated with high morbidity and mortality. Infections caused by this bacterium are becoming more difficult to treat due to increasing resistance to many of the available antibiotics. Ceftolozane–tazobactam and ceftazidime–avibactam are two new cephalosporin/β-lactamase inhibitor combination antimicrobials that have demonstrated excellent in vitro activity against several multi-drug-resistant pathogens, including multi-drug-resistant

P. aeruginosa

. Cases of infections with isolates of multi-drug-resistant

P. aeruginosa

that are resistant to both of these antimicrobials have rarely been reported. We report a case of mastoiditis caused by

P. aeruginosa

that was resistant to both ceftolozane–tazobactam and ceftazidime–avibactam.
Rariglobus hedericola gen. nov., sp. nov., belonging to the Verrucomicrobia, isolated from a temperate freshwater habitat
Authors: Pitt Alexandra , Schmidt Johanna , Koll Ulrike , Hahn Martin W.
Published: January 2020

The bacterial strain 53C-WASEF was isolated from a small freshwater ditch located in Eugendorf, Austria. Phylogenetic reconstructions with 16S rRNA gene sequences and genome based, with amino acid sequences obtained from 105 single copy genes, suggested that the strain represents a new genus and a new species within the family

Opitutaceae

, which belongs to the class

Opitutae

of the phylum

Verrucomicrobia

. Comparisons of the 16S rRNA gene sequence of strain 53C-WASEF with those of related type strains revealed a highest sequence similarity of 93.5 % to

Nibricoccus aquaticus

and of 92.9 % to

Geminisphaera colitermitum

. Interestingly, phylogentic trees indicated the latter as being the closest known relative of the new strain. Phenotypic, chemotaxonomic and genomic traits were investigated. Cells were observed to be small, spherical, motile and unpigmented, and grew chemoorganotrophically and aerobically. The respiratory quinone was MK-7, the predominant fatty acids were anteiso-C15 : 0, C16 : 1ω5c and C16 : 0. The identified polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Genome sequencing revealed genes putatively encoding for flagella synthesis and cellulose degradation. The genome size was 4.1 Mbp and the G+C content 60.6 mol%. For the new genus and the new species, we propose the name Rariglobus hedericola gen. nov., sp. nov. (=CIP 111665T=DSM 109123T).
ICTV Virus Taxonomy Profile: Chrysoviridae
Authors: Kotta-Loizou Ioly , Castón José R. , Coutts Robert H. A. , Hillman Bradley I. , Jiang Daohong , Kim Dae-Hyuk , Moriyama Hiromitsu , Suzuki Nobuhiro ,   ICTV Report Consortium
Published: January 2020

Members of the family Chrysoviridae are isometric, non-enveloped viruses with segmented, linear, dsRNA genomes. There are 3–7 genomic segments, each of which is individually encapsidated. Chrysoviruses infect fungi, plants and possibly insects, and may cause hypovirulence in their fungal hosts. Chrysoviruses have no known vectors and lack an extracellular phase to their replication cycle; they are transmitted via intracellular routes within an individual during hyphal growth, in asexual or sexual spores, or between individuals via hyphal anastomosis. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the family Chrysoviridae, which is available at ictv.global/report/chrysoviridae.
Cefuroxime pharmacokinetics and pharmacodynamics for intravenous dosage regimens with 750 mg or 1500 mg doses in healthy young volunteers
Authors: Thønnings Sara , Jensen Klaus S. , Nielsen Ninna B. , Skjønnemand Martin , Hansen Dennis S. , Lange Kai H. W. , Frimodt-Møller Niels
Published: January 2020

Introduction. Cefuroxime is an important antibiotic to treat several serious infections. Rapid elimination through the kidneys and the variation in MICs of various susceptible pathogens such as Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and

Streptococcus pneumoniae

give rise to dosing issues, especially in otherwise healthy patients.

Aim. To investigate the probability of target attainment (PTA) for obtaining the optimal dosage regimens for cefuroxime in healthy young people.

Methodology. Two weeks apart 750 and 1500 mg cefuroxime were administered as an intravenous bolus to 20 healthy volunteers (mean age: 27 years). Population modelling and simulation studies were done based on the obtained data for cefuroxime plasma concentration.

Results. With a target value of time above MIC (T
>MIC) greater than 50 % the simulations revealed that a PTA of >99 % is obtained for

S. pneumoniae

with a dosage regimen of 750 mg q12h. For

E. coli

and

K. pneumoniae

the PTA was <90 % even with the highest, simulated dosage of 1500 mg q6h. For

S. aureus

a dosage of 1500 mg q8h gave a PTA above 97 %.

Conclusions.

S. pneumoniae

is most likely treatable with a two-daily dose of 750 mg cefuroxime. Not treatable are

K. pneumoniae

and

E. coli

. For

S. aureus

1500 mg q8h constitutes an optimal dosing schedule.
Comparative genomics confirms a rare melioidosis human-to-human transmission event and reveals incorrect phylogenomic reconstruction due to polyclonality
Authors: Aziz Ammar , Currie Bart J. , Mayo Mark , Sarovich Derek S. , Price Erin P.
Published: January 2020

Human-to-human transmission of the melioidosis bacterium,

Burkholderia pseudomallei

, is exceedingly rare, with only a handful of suspected cases documented to date. Here, we used whole-genome sequencing (WGS) to characterize one such unusual

B. pseudomallei

transmission event, which occurred between a breastfeeding mother with mastitis and her child. Two strains corresponding to multilocus sequence types (STs)-259 and -261 were identified in the mother’s sputum from both the primary culture sweep and in purified colonies, confirming an unusual polyclonal infection in this patient. In contrast, primary culture sweeps of the mother’s breast milk and the child’s cerebrospinal fluid and blood samples contained only ST-259, indicating monoclonal transmission to the child. Analysis of purified ST-259 isolates showed no genetic variation between mother and baby isolates, providing the strongest possible evidence of

B. pseudomallei

human-to-human transmission, probably via breastfeeding. Next, phylogenomic analysis of all isolates, including the mother’s mixed ST-259/ST-261 sputum sample, was performed to investigate the effects of mixtures on phylogenetic inference. Inclusion of this mixture caused a dramatic reduction in the number of informative SNPs, resulting in branch collapse of ST-259 and ST-261 isolates, and several instances of incorrect topology in a global

B. pseudomallei

phylogeny, resulting in phylogenetic incongruence. Although phylogenomics can provide clues about the presence of mixtures within WGS datasets, our results demonstrate that this methodology can lead to phylogenetic misinterpretation if mixed genomes are not correctly identified and omitted. Using current bioinformatic tools, we demonstrate a robust method for bacterial mixture identification and strain parsing that avoids these pitfalls.
Procurement of innovation terminology usage in health care: A scoping review protocol
Authors: Andrews Margaret R. , Ramos Romualdo , Ahlberg Martina , Hazelzet Jan A. , van Raaij Erik M. , Sihag Vikrant , Alessandrello Rossana , Aurín Eva , Bakir Bahar , Carter Desmond , Ikävalko Suzan , Janian Mariet Nouri , Oleari Elettra , Timmermann Maarten M. , Valls-Comamala Victòria , Stamm Tanja A. ,   Platform for Innovation of Procurement and Procurement of Innovation Project
Published: January 2020

Background

Although procurement of innovation is an established policy tool used to stimulate collaboration between supply- and demand-side entities during the development of new technologies, there is little scientific literature describing the process as applied in health care settings. Furthermore, what literature exists contains inconsistencies of terms, definitions, and/or concepts related to procurement of innovation. This protocol details our process for a systematic scoping review to describe the current scope of literature and to provide terminology clarification.

Methods

A search strategy will be used to search PubMed, EMBASE [OVID], CINAHL [EBSCO], PsycINFO [ProQUEST], ABI/INFORM, ISI Web of Knowledge, EBSCO, JSTOR, the Cochrane Database of Systematic Reviews, and Google Scholar; grey literature, non-scientific reports, policy documents and expert recommendations will also be considered as additional sources for texts. Two researchers will screen titles and abstracts for inclusion/exclusion criteria, followed by full texts. We will extract the following data, if applicable: title, authors, date, author affiliations, country, journal/publication characteristics, setting, aims/purpose, methodology, sample characteristics, assessment/evaluation tools, outcome parameters, key findings, relevance, and terminology usage/definitions. Results will be presented narratively and visually.

Discussion

This paper describes the steps of our proposed systematic scoping review to identify and analyse scientific and non-scientific literature related to procurement of innovation and/or innovation of procurement in health care settings, with a particular focus on digital health technologies. Results are intended to demonstrate the current scope of literature, to provide clarity in language and therefore to serve as a first step for further research in this growing field.
Integration of New Information in Memory: New Insights from a Complementary Learning Systems Perspective
Authors: McClelland James L. , McNaughton Bruce L. , Lampinen Andrew K.
Published: January 2020

According to complementary learning systems theory, integrating new memories into the neocortex of the brain without interfering with what is already known depends on a gradual learning process, interleaving new items with previously learned items. However, empirical studies show that information consistent with prior knowledge can be integrated very quickly. We use artificial neural networks with properties like those we attribute to the neocortex to develop a theoretical understanding of the role of consistency with prior knowledge in putatively neocortex-like learning systems, providing new insights into when integration will be fast or slow and how integration might be made more efficient when the items to be learned are hierarchically structured. The work relies on deep linear networks that capture the qualitative aspects of the learning dynamics of the more complex non-linear networks used in previous work. The time course of learning in these networks can be linked to the hierarchical structure in the training data, captured mathematically as a set of dimensions that correspond to the branches in the hierarchy. In this context, a new item to be learned can be characterized as having aspects that project onto previously known dimensions, and others that require adding a new branch/dimension. The projection onto the known dimensions can be learned rapidly without interleaving, but learning the new dimension requires gradual interleaved learning. When a new item only overlaps with items within one branch of a hierarchy, interleaving can focus on the previously-known items within this branch, resulting in faster integration with less inter-leaving overall. The discussion considers how the brain might exploit these facts to make learning more efficient and highlights predictions about what aspects of new information might be hard or easy to learn.
AAV Ablates Neurogenesis in the Adult Murine Hippocampus
Authors: Johnston ST , Parylak SL , Kim S , Mac N , Lim CK , Gallina IS , Bloyd CW , Newberry A , Saavedra CD , Novák O , Gonçalves JT , Gage FH , Shtrahman M
Published: January 2020

Recombinant adeno-associated virus (rAAV) has been widely used as a viral vector across mammalian biology and has been shown to be safe and effective in human gene therapy. We demonstrate that neural progenitor cells (NPCs) and immature dentate granule cells (DGCs) within the adult murine hippocampus are particularly sensitive to rAAV-induced cell death. Cell loss is dose dependent and nearly complete at experimentally relevant viral titers. rAAV-induced cell death is rapid and persistent, with loss of BrdU-labeled cells within 18 hours post-injection and no evidence of recovery of adult neurogenesis at 3 months post-injection. The remaining mature DGCs appear hyperactive 4 weeks post-injection based on immediate early gene expression, consistent with previous studies investigating the effects of attenuating adult neurogenesis.In vitroapplication of AAV or electroporation of AAV2 inverted terminal repeats (ITRs) is sufficient to induce cell death. Efficient transduction of the dentate gyrus (DG)—without ablating adult neurogenesis—can be achieved by injection of rAAV2-retro serotyped virus into CA3. rAAV2-retro results in efficient retrograde labeling of mature DGCs and permitsin vivo2-photon calcium imaging of dentate activity while leaving adult neurogenesis intact. These findings expand on recent reports implicating rAAV-linked toxicity in stem cells and other cell types and suggest that future work using rAAV as an experimental tool in the DG and as a gene therapy for diseases of the central nervous system (CNS) should be carefully evaluated.
Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers
Authors: Cohen Alexander A. , Yang Zhi , Gnanapragasam Priyanthi NP , Ou Susan , Dam Kim-Marie A. , Wang Haoqing , Bjorkman Pamela J.
Published: January 2020

Current influenza vaccines do not elicit broadly protective immune responses against multiple strains. New strategies to focus the humoral immune response to conserved regions on influenza antigens are therefore required for recognition by broadly neutralizing antibodies. It has been suggested that B-cells with receptors that recognize conserved epitopes would be preferentially stimulated through avidity effects by mosaic particles presenting multiple forms of a variable antigen. We adapted SpyCatcher-based platforms, AP205 virus-like particles (VLPs) and mi3 nanoparticles (NPs), to covalently co-display SpyTagged hemagglutinin (HA) trimers from group 1 and group 2 influenza A strains. Here we show successful homotypic and heterotypic conjugation of up to 8 different HA trimers to both VLPs and NPs. We characterized the HA-VLPs and HA-NPs by cryo-electron tomography to derive the average number of conjugated HAs and their separation distances on particles, and compared immunizations of mosaic and homotypic particles in wild-type mice. Both types of HA particles elicited strong antibody responses, but the mosaic particles did not consistently elicit broader immune responses than mixtures of homotypic particles. We conclude that covalent attachment of HAs from currently-circulating influenza strains represents a viable alternative to current annual influenza vaccine strategies, but in the absence of further modifications, is unlikely to represent a method for making a universal influenza vaccine.
Nuclear Plasticity Increases Susceptibility to Damage During Confined Migration
Authors: Mukherjee Abhishek , Barai Amlan , Singh Ramesh K , Yan Wenyi , Sen Shamik
Published: January 2020

Large nuclear deformations during migration through confined spaces have been associated with nuclear membrane rupture and DNA damage. However, the stresses associated with nuclear damage remain unclear. Here, using a quasi-static plane strain finite element model, we map evolution of nuclear shape and stresses during confined migration of a cell through a deformable matrix. Plastic deformation of the nucleus observed for a cell with stiff nucleus transiting through a stiffer matrix lowered nuclear stresses, but also led to kinking of the nuclear membrane. In line with model predictions, transwell migration experiments with fibrosarcoma cells showed that while nuclear softening increased invasiveness, nuclear stiffening led to plastic deformation and higher levels of DNA damage. In addition to highlighting the advantage of nuclear softening during confined migration, our results suggest that plastic deformations of the nucleus during transit through stiff tissues may lead to bending-induced nuclear membrane disruption and subsequent DNA damage.
Potential short-term earthquake forecasting by farm-animal monitoring
Authors: Wikelski Martin , Mueller Uschi , Scocco Paola , Catorci Andrea , Desinov Lev , Belyaev Mikhail , Keim Daniel , Pohlmeier Winfried , Fechteler Gerhard , Mai P. Martin
Published: January 2020

Whether changes in animal behavior allow for short-term earthquake predictions has been debated for a long time. During the 2016/2017 earthquake sequence in Italy, we instrumentally observed the activity of farm animals (cows, dogs, sheep) close to the epicenter of the devastating magnitude M6.6 Norcia earthquake (Oct-Nov 2016) and over a subsequent longer observation period (Jan-Apr 2017). Relating 5304 (in 2016) and 12948 (in 2017) earthquakes with a wide magnitude range (0.4 ≤ M ≤ 6.6) to continuously measured animal activity, we detected how the animals collectively reacted to earthquakes. We also found consistent anticipatory activity prior to earthquakes during times when the animals were in a stable, but not during their time on a pasture. We detect these anticipatory patterns not only in periods with high, but also in periods of low seismic activity. Earthquake anticipation times (1-20hrs) are negatively correlated with the distance between the farm and earthquake hypocenters. Our study suggests that continuous instrumental monitoring of animal collectives has the potential to provide statistically reliable patterns of pre-seismic activity that could allow for short-term earthquake forecasting.

One Sentence Summary

A collective of domestic animals repeatedly showed unusually high activity levels before earthquakes, with anticipation times (1-20h) negatively related to distance from epicenters (5-28km).
Three major dimensions of human brain cortical ageing in relation to cognitive decline across the 8thdecade of life
Authors: Cox SR , Harris MA , Ritchie SJ , Buchanan CR , Valdés Hernández MC , Corley J , Taylor AM , Madole JW , Harris SE , Whalley HC , McIntosh AM , Russ TC , Bastin ME , Wardlaw JM , Deary IJ , Tucker-Drob EM
Published: January 2020

Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. However, cross-sectional brain data conflates information on ageing with patterns that are present throughout life. We characterised brain cortical ageing across the 8thdecade of life in a longitudinal ageing cohort, at ages ~73, ~76, and ~79 years, with a total of 1,376 MRI scans. Volumetricchangesamong cortical regions of interest (ROIs) were more strongly correlated (averager= 0.805, SD = 0.252) than werecross-sectionalvolumes of the same ROIs (averager= 0.350, SD = 0.178). We identified a broad, cortex-wide, dimension of atrophy that explained 66% of the variance in longitudinal changes across the cortex. Our modelling also discovered more specific fronto-temporal and occipito-parietal dimensions, that were orthogonal to the general factor and together explained an additional 20% of the variance. The general factor was associated with declines in general cognitive ability (r= 0.431,p< 0.001) and in the domains of visuospatial ability (r= 0.415,p= 0.002), processing speed (r= 0.383,p< 0.001) and memory (r= 0.372,p< 0.001). Individual differences in brain cortical atrophy with ageing are manifest across three broad dimensions of the cerebral cortex, the most general of which is linked with cognitive declines across domains. Longitudinal approaches are invaluable for distinguishing lifelong patterns of brain-behaviour associations from patterns that are specific to aging.
The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells
Authors: De Cecco Elena , Celauro Luigi , Vanni Silvia , Grandolfo Micaela , Aguzzi Adriano , Legname Giuseppe
Published: January 2020

Tauopathies are prevalent, invariably fatal brain diseases for which no cure is available. Tauopathies progressively affect the brain through cell-to-cell transfer of tau protein amyloids, yet the spreading mechanisms are unknown. Here we show that the cellular prion protein (PrPC) facilitates the uptake of tau aggregates by cultured cells, possibly by acting as an endocytic receptor. In mouse neuroblastoma cells, we found that tau amyloids bind to PrPC; internalization of tau fibrils was reduced in isogenic cells devoid of the gene encoding PrPC. Antibodies against N-proximal epitopes of PrPCimpaired the binding of tau amyloids and decreased their uptake. Surprisingly, exposure of chronically prion-infected cells to tau amyloids reduced the accumulation of aggregated prion protein; this effect lasted for more than 72 hours after amyloid removal. These results point to bidirectional interactions between the two proteins: whilst PrPCmediates the entrance of tau fibrils in cells, PrPScbuildup is greatly reduced in their presence, possibly because of an impairment in the prion conversion process.
Diagnostic of begomoviruses in complex infections –a case study
Authors: Jovel Juan
Published: January 2020

Complexes of viruses inducing a syndrome in plants strongly hinder the identification of the causal agent of a disease. TheSida micranthamosaic disease is associated with a complex of begomoviruses. For more than twenty years, two DNAs A (DNA A2 and DNA A3) belonging to this complex could neither be detected nor isolated fromSida micranthaSchr. plants, although one of them (DNA A2) now appears to be the major component of the complex. A random unintendedBemisia tabaci-mediated transmission of begomoviruses from several Sida species – includingS. micrantha– to experimentalMalva parvifloraplants resulted in the serendipitous finding of these new DNAs A. Simultaneously, a number of other begomoviruses infecting Sida plants from several Latin American countries were transmitted toM. parvifloraplants and the convergence of them resulted in natural pseudorecombinants. Pseudorecombination, however, took place exclusively between heterologous genomic components that shared identical binding sites for the replication-associated protein AC1. This case study constitutes an exceptional opportunity for the analysis of plant–virus– vector interactions in a quasi-natural environment. In addition to that, the methodology described here may be used to isolate and characterize different begomoviruses inducing a syndrome during mix infections.
Connecting secretome to hematopoietic stem cell phenotype shifts in an engineered bone marrow niche
Authors: Gilchrist Aidan E. , Harley Brendan A.C.
Published: January 2020

Hematopoietic stem cells (HSCs) primarily reside in the bone marrow, where they receive external cues from their local microenvironment. The complex milieu of biophysical cues, cellular components, and cell-secreted factors regulates the process by which HSC produce the blood and immune system. We previously showed direct co-culture of primary murine hematopoietic stem and progenitor cells with a population of marrow-derived mesenchymal stromal and progenitor cells (MSPCs) in a methacrylamide-functionalized gelatin (GelMA) hydrogel improves hematopoietic progenitor maintenance. However, the mechanism by which MSPCs influenced HSC fate decisions remained unknown. Herein, we report the use of proteomic analysis to correlate HSC phenotype to a broad candidate pool of 200 soluble factors produced by combined mesenchymal and hematopoietic progeny. Partial Least Squares Regression (PLSR), along with an iterative filter method, identified TGFβ-1, MMP-3, c-RP, and TROY as positively correlated with HSC maintenance. Experimentally, we then observe exogenous stimulation of HSC monocultures in GelMA hydrogels with these combined cytokines increases the ratio of hematopoietic progenitors to committed progeny after a 7-day culture 7.52 ± 3.65 fold compared to non-stimulated monocultures. Findings suggest a cocktail of the downselected cytokines amplify hematopoietic maintenance potential of HSCs beyond that of MSPC-secreted factors alone. This work integrates empirical and computation methods to identify cytokine combinations to improve HSC maintenance within an engineered HSC niche, suggesting a route towards identifying feeder-free culture platforms for HSC expansion.

Insight

Hematopoietic stem cells within an artificial niche receive maintenance cues in the form of soluble factors from hematopoietic and mesenchymal progeny. Applying a proteomic regression analysis, we identify a reduced set of soluble factors correlated to maintenance of a hematopoietic phenotype during culture in a biomaterial model of the bone marrow niche. We identify a minimum factor cocktail that promotes hematopoietic maintenance potential in a gelatin-based culture, regardless of the presence of mesenchymal feeder-cells. By combining empirical and computational methods, we report an experimentally feasible number of factors from a large dataset, enabling exogenous integration of soluble factors into an engineered hematopoietic stem cell for enhance maintenance potential of a quiescent stem cell population.
Exploring the remarkable diversity ofEscherichia coliPhages in the Danish Wastewater Environment, Including 91 Novel Phage Species
Authors: Olsen Nikoline S. , Kot Witold , Junco Laura M. F. , Hansen Lars H.
Published: January 2020

Phages drive bacterial diversity - profoundly influencing diverse microbial communities, from microbiomes to the drivers of global biogeochemical cycling. The vast genomic diversity of phages is gradually being uncovered as >8000 phage genomes have now been sequenced. Aiming to broaden our understanding ofEscherichia coli(MG1655, K-12) phages, we screened 188 Danish wastewater samples (0.5 ml) and identified 136 phages of which 104 are unique phage species and 91 represent novel species, including several novel lineages. These phages are estimated to represent roughly a third of the true diversity ofEscherichiaphages in Danish wastewater. The novel phages are remarkably diverse and represent four different familiesMyoviridae, Siphoviridae, PodoviridaeandMicroviridae. They group into 14 distinct clusters and nine singletons without any substantial similarity to other phages in the dataset. Their genomes vary drastically in length from merely 5 342 bp to 170 817 kb, with an impressive span of GC contents ranging from 35.3% to 60.0%. Hence, even for a model host bacterium, in the go-to source for phages, substantial diversity remains to be uncovered. These results expand and underlines the range ofEscherichiaphage diversity and demonstrate how far we are from fully disclosing phage diversity and ecology.
Three genomes of Osteoglossidae shed light on ancient teleost evolution
Authors: Hao Shijie , Han Kai , Meng Lingfeng , Huang Xiaoyun , Shi Chengcheng , Zhang Mengqi , Wang Yilin , Liu Qun , Zhang Yaolei , Seim Inge , Xu Xun , Liu Xin , Fan Guangyi
Published: January 2020

Osteoglossiformes is a basal clade of teleost, originated from late Jurassic and had seen the process of continental drift. The genomic differences amongst Osteoglossiformes species should reflect the unique evolve history of that time. Here, we presented the chromosome-level genome of Heterotis niloticus which is the only omnivore species of Osteoglossidae spreading in Africa. Together with other two Osteoglossidae species genomes of Arapaima gigas and Scleropages formosus which spread in South America and Australia respectively, we found great evolutionary differences in gene families and transposable elements. Phylogenetic analysis showed that the ancestor of H. niloticus and A. gigas diverged with S. formosus at ∼106.1Mya, consistent with the time of Afro-South American drift and A. gigas speciated from the ancestor of H. niloticus and A. gigas at ∼59.2 Mya, consistent with the separation of Eurasia and North American continents. And we proposed the evolutionary traces of Osteoglossidae species based on comparative genomics analysis and their living geographic habitats. We identified loss of LINEs and LTRs, fast evolutionary rate in parallel to fast pseudogenization rate in H. niloticus and A. gigas comparing to S. formosus during the evolutionary process. We also found notable OR genes contraction in H. niloticus, which might be related to the diet transition. Taken together, we reconstructed the evolutionary process of Osteoglossidae using three representative genomes, providing a possible clue for biogeographic and evolution study of ancient teleost clade.
Peg-in-hole assembly based on master-slave coordination for a compliant dual-arm robot
Authors: Huang Yanjiang , Zheng Yanglong , Wang Nianfeng , Ota Jun , Zhang Xianmin
Published: January 2020

Purpose

The paper aims to propose an assembly scheme based on master–slave coordination for a compliant dual-arm robot to complete a peg-in-hole assembly task.

Design/methodology/approach

The proposed assembly scheme is inspired by the coordinated behaviors of human beings in the assembly process. The left arm and right arm of the robot are controlled to move alternately. The fixed arm and the moving arm are distinguished as the slave arm and the master arm, respectively. The position control model is used at the uncontacted stage, and the torque control model is used at the contacted stage.

Findings

The proposed assembly scheme is evaluated through peg-in-hole assembly experiments with different shapes of assembly piece. The round, triangle and square assembly piece with 0.5 mm maximum clearance between the peg and the hole can be assembled successfully based on the proposed method. Furthermore, three assembly strategies are investigated and compared in the peg-in-hole assembly experiments with different shapes of assembly piece.

Originality/value

The contribution of this study is that the authors propose an assembly scheme for a compliant dual-arm robot to overcome the low positioning accuracy and complete the peg-in-hole assembly tasks with different shapes parts.