bluuebunny/crossref_metadata_2025 huggingface dataset:
Transduction catalysis: doxorubicin accelerates and enhances rAAV-mediated gene expression in the cortex of mouse, cat and monkey
Authors: Gong Hongliang , Yuan Nini , Shen Zhiming , Tang Cheng , Shipp Stewart , Qian Liling , Lu Yiliang , Andolina Ian Max , Zhang Shenghai , Wu Jihong , Yang Hui , Wang Wei
Published: June 2020

Rapid and efficient gene transduction via recombinant adeno-associated viruses (rAAVs) is highly desirable across many basic and clinical research domains. Here we report vector co-infusion with doxorubicin, a clinical anti-cancer drug, markedly enhanced rAAV-mediated gene expression in the cerebral cortex across mammalian species (cat, mouse, and macaque), acting throughout the time-period examined and detectable at just three days post-transfection. This enhancement showed serotype generality, being common to rAAV serotypes 2, 8, 9 and PHP.eB tested, and was observed both locally, and at remote locations consistent with doxorubicin undergoing retrograde axonal transport. All these effects were observed at doses matching human blood plasma levels in clinical therapy, and lacked detectable cytotoxicity as assessed by cell morphology, activity, apoptosis and behavioral testing. Altogether, this study identifies an effective means to improve the capability and scope ofin vivorAAV applications, accelerating and augmenting gene transduction at doxorubicin concentrations paralleling medical practice.

Highlights

Anti-cancer drug doxorubicin doubles the rate of rAAV-mediated transgene expression

Doxorubicin enhancement generalizes across rAAV serotypes and animal species

The effect is observed in both locally and retrogradely infected cortical neurons

The effective dosage is free from appreciable cytotoxicity and matches clinical settings
A genomic amplification affecting a carboxylesterase gene cluster confers organophosphate resistance in the mosquitoAedes aegypti: from genomic characterization to high-throughput field detection
Authors: Cattel Julien , Haberkorn Chloé , Laporte Fréderic , Gaude Thierry , Cumer Tristan , Renaud Julien , Sutherland Ian W. , Hertz Jeffrey C. , Bonneville Jean-Marc , Arnaud Victor , Noûs Camille , Fustec Bénédicte , Boyer Sébastien , Marcombe Sébastien , David Jean-Philippe
Published: June 2020

By altering gene expression and creating paralogs, genomic amplifications represent a key component of short-term adaptive processes. In insects, the use of insecticides can select gene amplifications causing an increased expression of detoxification enzymes, supporting the usefulness of these DNA markers for monitoring the dynamics of resistance alleles in the field. In this context, the present study aims to characterise a genomic amplification event associated with resistance to organophosphate insecticides in the mosquitoAedes aegyptiand to develop a molecular assay to monitor the associated resistance alleles in the field. An experimental evolution experiment using a composite population from Laos supported the association between the over-transcription of multiple contiguous carboxylesterase genes on chromosome 2 and resistance to multiple organophosphate insecticides. Combining whole genome sequencing and qPCR on specific genes confirmed the presence of a ~100 Kb amplification spanning at least five carboxylesterase genes at this locus with the co-existence of multiple structural duplication haplotypes. Field data confirmed their circulation in South-East Asia and revealed high copy number polymorphism among and within populations suggesting a trade-off between this resistance mechanism and associated fitness costs. A dual-colour multiplex TaqMan assay allowing the rapid detection and copy number quantification of this amplification event inAe. aegyptiwas developed and validated on field populations. The routine use of this novel assay will improve the tracking of resistance alleles in this major arbovirus vector.
IGD: high-performance search for large-scale genomic interval datasets
Authors: Feng Jianglin , Sheffield Nathan C.
Published: June 2020

Databases of large-scale genome projects now contain thousands of genomic interval datasets. These data are a critical resource for understanding the function of DNA. However, our ability to examine and integrate interval data of this scale is limited. Here, we introduce the integrated genome database (IGD), a method and tool for searching genome interval datasets more than three orders of magnitude faster than existing approaches, while using only one hundredth of the memory. IGD uses a novel linear binning method that allows us to scale analysis to billions of genomic regions.

Availability

https://github.com/databio/IGD
Mms19promotes spindle microtubule assembly in neural stem cells through two distinct pathways
Authors: Chippalkatti Rohan , Egger Boris , Suter Beat
Published: June 2020

Mitotic divisions depend on the timely assembly and proper orientation of the mitotic spindle. Malfunctioning of these processes can considerably delay mitosis, thereby compromising tissue growth and homeostasis, and leading to chromosomal instability. Here we identified Mms19 as an important player in these processes as it promotes spindle and astral microtubule (MT) growth and consequently regulates spindle orientation and mitosis duration inDrosophilaneural stem cells. Loss of functionalMms19drastically affects the growth and development of mitotic tissues inDrosophilalarvae. We found thatMms19performs its mitotic activities through two different pathways. By stimulating the mitotic kinase cascade, it triggers the localization of the MT regulatory complex TACC/Msps (Transforming Acidic Coiled Coil/Minispindles, the homolog of human ch-TOG) to the centrosome. In addition, we present evidence that Mms19 stimulates MT stability and bundling by binding directly to MTs.
Bacterivorous nematodes correlate with soil fertility and improved crop production in an organic minimum tillage system
Authors: Schmidt Jan H. , Hallmann Johannes , Finckh Maria R.
Published: June 2020

Organic farming systems are generally based on intensive soil tillage for seed bed preparation and weed control, which in the long-term often leads to reduced soil fertility. To avoid this, organic farming systems need to adopt conservation agriculture practices, such as minimum tillage and diligent crop rotations. However, minimum tillage generally delays soil warming in spring causing reduced nitrogen mineralization and thus poor plant growth. This negative effect needs to be compensated. We hypothesize that, in a diverse crop rotation, organic minimum tillage based on frequent cover cropping and application of dead mulch will improve soil fertility and thus crop production as confirmed by a number of chemical and biological soil indicators.

We made use of two long-term field experiments that compare typical organic plough-based systems (25 cm) with minimum tillage systems (<15 cm) including application of transfer mulch to potatoes. Both tillage systems were either fertilized with compost or equivalent amounts of mineral potassium and phosphate. In 2019, soil samples from both fields were collected and analyzed for soil pH, organic carbon, macro-, micronutrients, microbial biomass, microbial activity and total nematode abundance. In addition, performance of pea in the same soils was determined under greenhouse conditions.

Results from the field experiments showed an increase of macronutrients (+52%), micronutrients (+11%), microbial biomass (+51%), microbial activity (+86%), and bacterivorous nematodes (+112%) in minimum tillage compared with the plough-based system. In the accompanying greenhouse bioassay, pea biomass was 45% higher under minimum than under plough tillage. In conclusion, the study showed that under organic conditions, soil fertility can be improved in minimum tillage systems by intensive cover cropping and application of dead mulch to levels higher than in a plough-based system. Furthermore, the abundance of bacterivorous nematodes can be used as a reliable indicator for the soil fertility status.
Long-distance dispersal of oilseed rape seeds: The role of grain trailers
Authors: Bailleul Diane , Ollier Sébastien , Lecomte Jane
Published: June 2020

In agroecosystems, anthropogenic activities can modify the natural dispersal capacity of crops and their capacity to establish feral populations. In the case of oilseed rape (OSR), seed spillage from grain trailers during harvest was first quantified by anin situscientific study (Selommes, Loir-et-Cher, France). Demographic analysis of seeds collected from 85 traps set on road verges suggested that OSR dispersal distance due to seed spillage from grain trailers can be up to 400m. In the present study, we used SSR markers to genotype seeds collected from trap-sites and from surrounding OSR fields to precisely estimate the distances between traps and fields. Trailer directions on each road were also considered. Few seeds (5.8%) were not linked to a field in the studied area, while most of the seeds (59.2%) were linked to a field situated over 400 m away. The overall mean dispersal distance was 1250 m. It ranged from 308 m to 1392 m for one-lane roads, and from 1048 m to 1404 m for two-lane roads. Events of seed dispersal at greater distances (> 5 km) were rare but still possible. It thus follows that OSR seed dispersal due to spillage from grain trailers should be carefully considered in the context of genetically modified plant cultivation.
The role of dermis resident macrophages and their interaction with neutrophils in the early establishment ofLeishmania majorinfection transmitted by sand fly bite
Authors: Chaves Mariana M. , Lee Sang Hun , Kamenyeva Olena , Ghosh Kashinath , Sacks David
Published: June 2020

There is substantial experimental evidence to indicate thatLeishmaniainfections that are transmitted naturally by the bites of infected sand flies differ in fundamental ways from the inflammatory and immune reactions initiated by needle inocula. We have used flow cytometry and intravital microscopy (IVM) to reveal the heterogeneity of sand fly transmission sites with respect to the subsets of phagocytes in the skin that harborL. majorwithin the first hours and days after infection. By flow cytometry analysis, dermis resident macrophages (TRMs) were on average the predominant infected cell type at 1 hr and 24 hr. By confocal IVM, the co-localization ofL. majorand neutrophils varied depending on the proximity of deposited parasites to the presumed site of vascular damage, defined by the highly localized swarming of neutrophils. Some of the dermal TRMs could be visualized acquiring their infections via transfer from or efferocytosis of parasitized neutrophils, providing direct evidence for the “Trojan Horse” model. The role of neutrophil engulfment by dermal TRMs and the involvement of the Tyro3/Axl/Mertk family of receptor tyrosine kinases in these interactions and in sustaining the anti-inflammatory program of dermal TRMs was supported by the effects observed in neutrophil depleted and inAxl-/-Mertk-/-mice. TheAxl-/-Mertk-/-mice also displayed reduced parasite burdens but more severe pathology followingL. majorinfection transmitted by sand fly bite.

Sand flies transmitLeishmania majorwhich causes cutaneous leishmaniasis in humans and in non-human hosts. Our analyses of sand fly transmission sites ofL. majorin the mouse skin revealed that dermis resident macrophages (TRM) were the predominant phagocytes to take up the parasite within the first 24 hr post-bite. The early involvement of neutrophils varied depending on the proximity of deposited parasites to the site of tissue damage around which the neutrophils coalesced. By intra-vital microscopy, some of the dermal TRMs could be visualized acquiring their infections by direct transfer from or phagocytosis of parasitized neutrophils. The involvement of the Tyro3/Axl/Mertk family of receptor tyrosine kinases in these cellular interactions and in sustaining the anti-inflammatory functions of dermal TRMs was supported by the reduced parasite burdens but more severe pathology observed inAxl-/-Mertk-/-mice. The heterogeneity of sand fly transmission sites with respect to the dose of parasites and the early cellular interactions described here likely contribute to the wide range of infection outcomes that are associated with natural transmission ofL. majorobserved in mouse models and possibly humans.
A ChIP-exo screen of 887 PCRP transcription factor antibodies in human cells
Authors: Lai William K. M. , Mariani Luca , Rothschild Gerson , Smith Edwin R. , Venters Bryan J. , Blanda Thomas R. , Kuntala Prashant K. , Bocklund Kylie , Mairose Joshua , Dweikat Sarah N , Mistretta Katelyn , Rossi Matthew J. , James Daniela , Anderson James T. , Phanor Sabrina K. , Zhang Wanwei , Zhao Zibo , Shah Avani P. , Novitzky Katherine , McAnarney Eileen , Keogh Michael-C. , Shilatifard Ali , Basu Uttiya , Bulyk Martha L. , Pugh B. Franklin
Published: June 2020

Antibodies offer a powerful means to interrogate specific proteins in a complex milieu. However, antibody availability and reliability are problematic and epitope tagging can be impractical in many cases. In an effort to improve this situation, the Protein Capture Reagents Program (PCRP) generated over a thousand renewable monoclonal antibodies (mAbs) against human-presumptive chromatin proteins. However, these reagents have not been widely field-tested. We therefore performed a screen to test their ability to enrich genomic regions via chromatin immunoprecipitation (ChIP) and a variety of orthogonal assays. 887 unique antibodies against 681 unique human transcription factors (TFs), were assayed by ultra-high resolution ChIP-exo/seq, primarily in a single pass in one cell type (K562). Deep systematic analyses of the resulting ∼1,200 ChIP-exo datasets can be found atwww.PCRPvalidation.org. Subsets of PCRP mAbs were further tested in ChIP-seq, CUT&RUN, STORM super-resolution microscopy, immunoblots, and protein binding microarray (PBM) experiments. About 5% of the tested antibodies displayed target (i.e., cognate antigen) enrichment across at least one assay and are strong candidates for additional validation. An additional 34% produced ChIP-exo data that was distinct from background and thus warrant further testing. The remaining 61% were not substantially different from background, and likely require consideration of a much broader survey of cell types and/or assay optimizations. We demonstrate and discuss the metrics and challenges to antibody validation in chromatin-based assays.
D936Y and Other Mutations in the Fusion Core of the SARS-Cov-2 Spike Protein Heptad Repeat 1 Undermine the Post-Fusion Assembly
Authors: Cavallo Luigi , Oliva Romina
Published: June 2020

The iconic “red crown” of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is made of its spike (S) glycoprotein. The S protein is the Trojan horse of coronaviruses, mediating their entry into the host cells. While SARS-CoV-2 was becoming a global threat, scientists have been accumulating data on the virus at an impressive pace, both in terms of genomic sequences and of three-dimensional structures. On April 21st, the GISAID resource had collected 10,823 SARS-CoV-2 genomic sequences. We extracted from them all the complete S protein sequences and identified point mutations thereof. Six mutations were located on a 14-residue segment (929-943) in the “fusion core” of the heptad repeat 1 (HR1). Our modeling in the pre- and post-fusion S protein conformations revealed, for three of them, the loss of interactions stabilizing the post-fusion assembly. On May 29th, the SARS-CoV-2 genomic sequences in GISAID were 34,805. An analysis of the occurrences of the HR1 mutations in this updated dataset revealed a significant increase for the S929I and S939F mutations and a dramatic increase for the D936Y mutation, which was particularly widespread in Sweden and Wales/England. We notice that this is also the mutation causing the loss of a strong inter-monomer interaction, the D936-R1185 salt bridge, thus clearly weakening the post-fusion assembly.
An optogenetic method for interrogating YAP1 and TAZ nuclear-cytoplasmic shuttling
Authors: Dowbaj Anna M. , Jenkins Robert P. , Heddleston John M. , Ciccarelli Alessandro , Fallesen Todd , Hahn Klaus , Montagner Marco , Sahai Erik
Published: June 2020

The shuttling of transcription factors and transcriptional regulators in and out of the nucleus is central to the regulation of many biological processes. Here we describe a new method for studying the rates of nuclear entry and exit of transcriptional regulators. A photo-responsive AsLOV (Avena sativaLight Oxygen Voltage) domain is used to sequester fluorescently-labelled transcriptional regulators YAP1 and TAZ/WWTR1 on the surface of mitochondria and reversibly release them upon blue light illumination. After dissociation, fluorescent signals from mitochondria, cytoplasm and nucleus are extracted with a bespoke app and used to generate rates of nuclear entry and exit. Using this method, we demonstrate that phosphorylation of YAP1 on canonical sites enhances its rate of nuclear export. Moreover, we provide evidences that, despite high intercellular variability, YAP1 import and export rates correlated within the same cell. By simultaneously releasing YAP1 and TAZ from sequestration, we show that their rates of entry and exit are correlated. Furthermore, tracking of light-sensitive YAP1 with lattice lightsheet microscopy revealed high heterogeneity of YAP1 dynamics within different subcellular regions, suggesting that implementing high resolution volumetric 3D data could shed light on new mechanisms of nuclear-cytoplasmic shuttling of proteins.
Slow oscillation-spindle coupling is negatively associated with emotional memory formation following stress
Authors: Denis Dan , Kim Sara Y. , Kark Sarah M. , Daley Ryan T. , Kensinger Elizabeth A. , Payne Jessica D.
Published: June 2020

Both stress and sleep enhance emotional memory. They also interact, with the largest effect of sleep on emotional memory being seen when stress occurs shortly before or after encoding. Slow wave sleep (SWS) is critical for long-term episodic memory, facilitated by the temporal coupling of slow oscillations and sleep spindles. Prior work in humans has shown these associations for neutral information in non-stressed participants. Whether coupling interacts with stress to facilitate emotional memory formation is unknown. Here, we addressed this question by reanalyzing an existing dataset of 64 individuals. Participants underwent a psychosocial stressor (32) or comparable control (32) prior to the encoding of 150-line drawings of neutral, positive, and negative images. All participants slept overnight with polysomnography, before being given a surprise memory test the following day. In the stress group, time spent in SWS was positively correlated with memory for images of all valences. Results were driven by those who showed a high cortisol response to the stressor, compared to low responders. The amount of slow oscillation-spindle coupling during SWS was negatively associated with neutral and emotional memory in the stress group only. The association with emotional memory was significantly stronger than for neutral memory within the stress group. These results suggest that stress around the time of initial memory formation impacts the relationship between slow wave sleep and memory.
Feature Extraction Approaches for Biological Sequences: A Comparative Study of Mathematical Models
Authors: Bonidia Robson Parmezan , Sampaio Lucas Dias Hiera , Domingues Douglas Silva , Paschoal Alexandre Rossi , Lopes Fabrício Martins , de Leon Ferreira de Carvalho André Carlos Ponce , Sanches Danilo Sipoli
Published: June 2020

The number of available biological sequences has increased significantly in recent years due to various genomic sequencing projects, creating a huge volume of data. Consequently, new computational methods are needed to analyze and extract information from these sequences. Machine learning methods have shown broad applicability in computational biology and bioinformatics. The utilization of machine learning methods has helped to extract relevant information from various biological datasets. However, there are still several obstacles that motivate new algorithms and pipeline proposals, mainly involving feature extraction problems, in which extracting significant discriminatory information from a biological set is challenging. Considering this, our work proposes to study and analyze a feature extraction pipeline based on mathematical models (Numerical Mapping, Fourier, Entropy, and Complex Networks). As a case study, we analyze Long Non-Coding RNA sequences. Moreover, we divided this work into two studies, e.g., (I) we assessed our proposal with the most addressed problem in our review, e.g., lncRNA vs. mRNA; (II) we tested its generalization on different classification problems, e.g., circRNA vs. lncRNA. The experimental results demonstrated three main contributions: (1) An in-depth study of several mathematical models; (2) a new feature extraction pipeline and (3) its generalization and robustness for distinct biological sequence classification.
Invasion history ofHarmonia axyridis(Pallas, 1773) (Coleoptera: Coccinellidae) in Ecuador
Authors: Cisneros-Heredia Diego F. , Peñaherrera-Romero Emilia
Published: June 2020

Harmonia axyridisis a ladybird extensively used around the world for biological control of agricultural pest. However, it has become invasive in several countries, producing negative ecological and socio-economic impacts. Herein, we review the invasion history of the Harlequin LadybirdHarmonia axyridis(Pallas, 1773) in Ecuador. Although first reported in Ecuador in 2012, museum specimens date back to 2004 and it is currently established across the country, especially along the Andean region. Due to its invasive nature, further studies are urgently needed to evaluate possible impacts ofH. axyridison the Ecuadorian biodiversity and agroindustry.
Hurricane-induced demographic changes in a nonhuman primate population
Authors: Morcillo Dana O. , Steiner Ulrich K. , Grayson Kristine L. , Ruiz-Lambides Angelina V. , Hernández-Pacheco Raisa
Published: June 2020

Major disturbance events can have large impacts on the demography and dynamics of animal populations. Hurricanes are one example of an extreme climatic event, predicted to increase in frequency due to climate change, and thus expected to be a considerable threat to population viability. However, little is understood about the underlying demographic mechanisms shaping population response following these extreme disturbances. Here, we analyze 45 years of the most comprehensive free-ranging nonhuman primate demographic dataset to determine the effects of major hurricanes on the variability and maintenance of long-term population fitness. For this, we use individual-level data to build matrix population models and perform perturbation analyses. Despite reductions in population growth rate mediated through reduced fertility, our study reveals a demographic buffering during hurricane years. As long as survival does not decrease, our study shows that hurricanes do not result in detrimental effects at the population level, demonstrating the unbalanced contribution of survival and fertility to population fitness in long-lived animal populations.
Spritz: A Proteogenomic Database Engine
Authors: Cesnik Anthony J. , Miller Rachel M. , Ibrahim Khairina , Lu Lei , Millikin Robert J. , Shortreed Michael R. , Frey Brian L. , Smith Lloyd M.
Published: June 2020

Proteoforms are the workhorses of the cell, and subtle differences between their amino acid sequence or post-translational modifications (PTMs) can change their biological function. To most effectively identify and quantify proteoforms in genetically diverse samples by mass spectrometry (MS), it is advantageous to search the MS data against a sample-specific protein database that is tailored to the sample being analyzed, in that it contains the correct amino acid sequences and relevant PTMs for that sample. To this end, we have developed Spritz (https://smith-chem-wisc.github.io/Spritz/), an open-source software tool for generating protein databases annotated with sequence variations and PTMs. We provide a simple graphical user interface (GUI) for Windows and scripts that can be run on any operating system. Spritz automatically sets up and executes approximately 20 tools, which enable construction of a proteogenomic database from only raw RNA sequencing data. Sequence variations that are discovered in RNA sequencing data upon comparison to the Ensembl reference genome are annotated on proteins in these databases, and PTM annotations are transferred from UniProt. Modifications can also be discovered and added to the database using bottom-up mass spectrometry data and global PTM discovery in MetaMorpheus. We demonstrate that such sample-specific databases allow the identification of variant peptides, modified variant peptides, and variant proteoforms by searching bottom-up and top-down proteomic data from the Jurkat human T lymphocyte cell line and demonstrate the identification of phosphorylated variant sites with phosphoproteomic data from the U2OS human osteosarcoma cell line.
Segmented K-Space Blipped-Controlled Aliasing in Parallel Imaging (Skipped-CAIPI) for High Spatiotemporal Resolution Echo Planar Imaging
Authors: Stirnberg Rüdiger , Stöcker Tony
Published: June 2020

Purpose

A segmented k-space blipped-CAIPI (skipped-CAIPI) sampling strategy for echo planar imaging (EPI) is proposed, which allows for a flexible choice of EPI factor and phase encode bandwidth independent of the controlled aliasing (CAIPIRINHA) pattern.

Theory and Methods

With previously proposed approaches, exactly two EPI trajectories were possible given a specific CAIPIRINHA pattern: either with slice gradient blips (blipped-CAIPI), or following a shot-selective approach (higher resolution). Recently, interleaved multi-shot segmentation along shot-selective CAIPI trajectories has been applied for high-resolution anatomical imaging. For more flexibility and a broader range of applications, we propose segmentation along any blipped-CAIPI trajectory. Thus, all EPI factors and phase encode bandwidths available with traditional segmented EPI can be combined with controlled aliasing.

Results

Temporal signal-to-noise ratios of moderate-to-high-resolution time series acquisitions at varying undersampling factors demonstrate beneficial sampling alternatives to blipped-CAIPI or shot-selective CAIPI. Rapid high-resolution scans furthermore demonstrate SNR-efficient and motion-robust structural imaging with almost arbitrary EPI factor and minimal noise penalty.

Conclusions

Skipped-CAIPI sampling increases protocol flexibility for high spatiotemporal resolution EPI. In terms of signal-to-noise ratio and efficiency, high-resolution functional or structural scans benefit vastly from a free choice of the CAIPIRINHA pattern. Even at moderate resolutions, the independence of sampling pattern, echo time and image matrix size is valuable for optimized functional protocol design. Although demonstrated with 3D-EPI, skipped-CAIPI is also applicable with simultaneous multislice EPI.
Quantifying fluorescent glycan uptake to elucidate strain-level variability in foraging behaviors of rumen bacteria
Authors: Klassen Leeann , Reintjes Greta , Tingley Jeffrey P. , Jones Darryl R. , Hehemann Jan-Hendrik , Smith Adam D. , Schwinghamer Timothy D. , Arnosti Carol , Jin Long , Alexander Trevor W. , Amundsen Carolyn , Thomas Dallas , Amann Rudolf , McAllister Tim A. , Abbott D. Wade
Published: June 2020

Gut microbiomes have vast catabolic potential and are essential to host health and nutrition. An in-depth understanding of the metabolic pathways in these ecosystems will enable us to design treatments (i.e. prebiotics) that influence microbiome structure and enhance host physiology. Currently, the investigation of metabolic pathways relies on inferences derived from metagenomics orin vitrocultivations, however, novel approaches targeting specific cell physiologies can illuminate the functional potential encoded within microbial (meta)genomes to accurately assess metabolic abilities. Here, we present a multi-faceted study using complimentary next-generation physiology and ‘omics’ approaches to characterize the microbial adaptation to a prebiotic in the rumen ecosystem. Using fluorescently labeled polysaccharides, we identified bacteria that actively metabolize a glycan prebiotic in the rumen microbiomeex vivo. Subsequently, we characterized strain-level variability in carbohydrate utilization systems and predict metabolic strategies of isolated bovine-adapted strains ofBacteroides thetaiotaomicronusing comparative whole genome sequencing, RNA-Seq, and carbohydrate-active enzyme fingerprinting.
Integrating remote sensing and jurisdictional observation networks to improve the resolution of ecological management
Authors: Townsend Philip A. , Clare John , Liu Nanfeng , Stenglein Jennifer L. , Anhalt-Depies Christine , Van Deelen Timothy R. , Gilbert Neil A. , Singh Aditya , Martin Karl J. , Zuckerberg Benjamin
Published: June 2020

The emergence of citizen science, passive sensors (e.g., trail cameras and acoustic monitoring), and satellite remote sensing have enabled biological data to be collected at unprecedented spatial and temporal scales. There is growing interest in networking these datastreams to expedite the collection and synthesis of environmental and biological data to improve broad-scale ecological monitoring, but there are no examples of such networks being developed to directly inform decision-making by managing agencies. Here, we present the implementation of one such jurisdictional observation network (JON), Snapshot Wisconsin (SW), that links satellite remote sensing (RS) with a volunteer-based trail camera network to generate new insights into wildlife distributions and improve their management by the state agency. SW relies on citizen scientists to deploy trail cameras across the state and classify images of wildlife. As of early 2020 SW comprises nearly 1800 volunteers hosting >2100 active cameras recording >37 million images across a sampling effort of >2000 combined trap-years at >3300 distinct camera locations. We use a set of case studies to demonstrate the potential power of a JON to monitor wildlife with unprecedented combinations of spatial, temporal, and biological resolution and extent. Specifically, we demonstrate that SW markedly improves the spatial and temporal resolution with which black bear distributions can be monitored or forecast, in turn improving the resolution of decision-making. Enhancing the biological resolution of monitoring (e.g., monitoring the distribution of species traits or behaviors) may provide new insights into population drivers, such as the connection between vegetation productivity and white-tailed deer foraging behaviors. Enhanced taxonomic extent provided by trail cameras and other passive sensor networks provide managers new information for a wide range of species and communities that are not otherwise monitored. Our cases further show that JONs synergize existing monitoring practices by serving as a complementary and independent line of evidence or as a tool to enhance the extent and precision of existing models through integrated modeling approaches. SW and other JONS are a powerful new tool for agencies to better achieve their missions and reshape the nature of environmental decision-making.
Mineral density differences between femoral cortical bone and trabecular bone are not explained by turnover rate alone
Authors: Lerebours Chloé , Weinkamer Richard , Roschger Andreas , Buenzli Pascal R.
Published: June 2020

Bone mineral density distributions (BMDDs) are a measurable property of bone tissues that depends strongly on bone remodelling and mineralisation processes. These processes can vary significantly in health and disease and across skeletal sites, so there is high interest in analysing these processes from experimental BMDDs. Here, we propose a rigorous hypothesis-testing approach based on a mathematical model of mineral heterogeneity in bone due to remodelling and mineralisation, to help explain differences observed between the BMDD of human femoral cortical bone and the BMDD of human trabecular bone. Recent BMDD measurements show that femoral cortical bone possesses a higher bone mineral density, but a similar mineral heterogeneity around the mean compared to trabecular bone. By combining this data with the mathematical model, we are able to test whether this difference in BMDD can be explained by (i) differences in turnover rate; (ii) differences in osteoclast resorption behaviour; and (iii) differences in mineralisation kinetics between the two bone types. We find that accounting only for differences in turnover rate is inconsistent with the fact that both BMDDs have a similar spread around the mean, and that accounting for differences in osteoclast resorption behaviour leads to biologically inconsistent bone remodelling patterns. We conclude that the kinetics of mineral accumulation in bone matrix must therefore be different in femoral cortical bone and trabecular bone. Although both cortical and trabecular bone are made up of lamellar bone, the different mineralisation kinetics in the two types of bone point towards more profound structural differences than usually assumed.
Total workflows of the single-molecule imaging analysis in living cells: a tutorial guidance to the measurement of the drug effects on a GPCR
Authors: Yanagawa Masataka , Sako Yasushi
Published: June 2020

Single-molecule imaging (SMI) is a powerful method to measure the dynamics of membrane proteins on the cell membrane. The single-molecule tracking (SMT) analysis provides information about the diffusion dynamics, the oligomer size distribution, and the particle density change. The affinity and on/off-rate of a protein—protein interaction can be estimated from the dual-color SMI analysis. However, it is difficult for trainees to determine quantitative information from the SMI movies. The present protocol guides the detailed workflows to measure the drug-activated dynamics of a G protein-coupled receptor (GPCR) and metabotropic glutamate receptor 3 (mGluR3), by using the total internal reflection fluorescence microscopy (TIRFM). This tutorial guidance comprises an open-source software named smDynamicsAnalyzer, with which one can easily analyze the SMT dataset by just following the workflows after building a designated folder structure (https://github.com/masataka-yanagawa/IgorPro8-smDynamicsAnalyzer).
SARS-CoV-2 placental infection and inflammation leading to fetal distress and neonatal multi-organ failure in an asymptomatic woman
Authors: Schoenmakers Sam , Snijder Pauline , Verdijk Robert M. , Kuiken Thijs , Kamphuis Sylvia S.M. , Koopman Laurens P. , Krasemann Thomas B. , Rousian Melek , Broekhuizen Michelle , Steegers Eric A.P. , Koopmans Marion P.G. , Fraaij Pieter L.A. , Reiss Irwin K.M.
Published: June 2020

Introduction

In general SARS-CoV-2-infection during pregnancy is not considered to be an increased risk for severe maternal outcomes, but has been associated with an increased risk for fetal distress. So far, there is no direct evidence of intrauterine vertical transmission and the mechanisms leading to the adverse outcomes are not well understood

Results

An asymptomatic pregnant woman with preterm fetal distress during the COVID19 pandemic was included. We obtained multiple maternal, placental and neonatal swabs, which showed a median viral load in maternal blood, urine, oropharynx, fornix posterior over a period of 6 days was 5.0 log copies /mL. The maternal side of the placenta had a viral load of 4.42 log copies /mL, while the fetal side had 7.15 log copies /mL. Maternal breast milk, feces and all neonatal samples tested negative. Serology of immunoglobulins against SARS-CoV-2 was tested positive in maternal blood, but negative in umbilical cord and neonatal blood. Pathological examination of the placenta included immunohistochemical investigation against SARS-CoV-2 antigen expression in combination with SARS-CoV-2 RNA in situ hybridization and transmission electron microscopy. It showed the presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the syncytiotrophoblasts.

Discussion

Placental infection by SARS-CoV-2 lead to fibrin depositions hampering fetal-maternal gas exchange most likely resulted in fetal distress necessitating a premature emergency caesarean section. Postpartum, the neonate showed a clinical presentation resembling a pediatric inflammatory multisystem syndrome including coronary artery ectasia, most likely associated with SARS-CoV-2 (PIMS-TS) for which admittance and care on the Neonatal Intensive Care unit (NICU) was required, despite being negative for SARS-CoV-2. This highlights the need for awareness of adverse fetal and neonatal outcomes during the current COVID-19 pandemic, especially considering that the majority of pregnant women appear asymptomatic.
Image-based modelling of inhaler deposition during respiratory exacerbation
Authors: Williams Josh , Kolehmainen Jari , Cunningham Steve , Ozel Ali , Wolfram Uwe
Published: June 2020

For many of the one billion sufferers of respiratory diseases worldwide, managing their disease with inhalers improves their ability to breathe. Poor disease management and rising pollution can trigger exacerbations which require urgent relief. Higher drug deposition in the throat instead of the lungs limits the impact on patient symptoms. To optimise delivery to the lung, patient-specific computational studies of aerosol inhalation can be used. How-ever in many studies, inhalation modelling does not represent an exacerbation, where the patient’s breath is much faster and shorter. Here we compare differences in deposition of inhaler particles (10, 4 µm) in the airways of a healthy male, female lung cancer and child cystic fibrosis patient. We aimed to evaluate deposition differences during an exacerbation compared to healthy breathing with image-based healthy and diseased patient models. We found that the ratio of drug in the lower to upper lobes was 35% larger during healthy breathing than an exacerbation. For smaller particles the upper airway deposition was similar in all patients, but local deposition hotspots differed in size, location and intensity. Our results identify that image-based airways must be used in respiratory modelling. Various inhalation profiles should be tested for optimal prediction of inhaler deposition.

Highlights

Regional and local drug deposition was modelled in three patients during normal, sinusoidal inhalation and an exacerbation.

Local drug deposition changes with airway shape and inhalation profile, even when regional deposition is similar.

Image-based models were combined with highly-resolved particle tracking including particle contact and cohesion.

Fluid model validated by comparing gas velocity field with in vitro experiments.
Hydroxychloroquine inhibits trained immunity – implications for COVID-19
Authors: Rother Nils , Yanginlar Cansu , Lindeboom Rik G.H. , Bekkering Siroon , van Leent Mandy M.T. , Buijsers Baranca , Jonkman Inge , de Graaf Mark , Baltissen Marijke , Lamers Lieke A. , Riksen Niels P. , Fayad Zahi A. , Mulder Willem J.M. , Hilbrands Luuk B. , Joosten Leo A.B. , Netea Mihai G. , Vermeulen Michiel , van der Vlag Johan , Duivenvoorden Raphaël
Published: June 2020

SARS-CoV-2 infection can cause severe disease for which currently no specific therapy is available. The use of hydroxychloroquine to prevent or treat SARS-CoV-2 infection is controversial and its mode of action poorly understood. We demonstrate that hydroxychloroquine inhibits trained immunity at the functional and epigenetic level and is accompanied by profound changes in the cellular lipidome as well as reduced expression of interferon-stimulated genes. Trained immunity comprises a functional adaptation induced by epigenetic reprogramming which facilitates the anti-viral innate immune response. Our findings therefore suggest that hydroxychloroquine may not have a beneficial effect on the anti-viral immune response to SARS-CoV-2.
Motivation and Cognitive Abilities as Mediators between Polygenic Scores and Psychopathology in Children
Authors: Pat Narun , Riglin Lucy , Anney Richard , Wang Yue , Barch Deanna M. , Thapar Anita , Stringaris Argyris
Published: June 2020

Objective

Fundamental questions in biological psychiatry concern the mechanisms that mediate between genetic liability and psychiatric symptoms. Genetic liability for many common psychiatric disorders often confers transdiagnostic risk to develop a wide variety of psychopathological symptoms through yet unknown pathways. We examine the psychological and cognitive pathways that might mediate the relationship between genetic liability (indexed by polygenic scores; PS) and broad psychopathology (indexed by p factor and its underlying dimensions).

Method

We first identified which of the common psychiatric PSs (major depressive disorder [MDD], attention-deficit/hyperactivity disorder [ADHD], anxiety, bipolar, schizophrenia, autism) were associated with p factor. We then focused on three pathways: punishment sensitivity (reflected by behavioral inhibition system; BIS), reward sensitivity (reflected by behavioral activation system; BAS) and cognitive abilities (reflected by g factor based on 10 neurocognitive tasks). We applied structural equation modeling on the Adolescent Brain Cognitive Development (ABCD) dataset (n=4,814; 2,263 female children; 9-10 years old).

Results

MDD and ADHD PSs were associated with p factor. The association between MDD PS and psychopathology was partially mediated by punishment sensitivity and cognitive abilities: proportion mediated= 22.35%. Conversely, the influence of ADHD PS on psychopathology was partially mediated by reward sensitivity and cognitive abilities: proportion mediated=30.04%. The mediating role of punishment sensitivity was specific to the emotional/internalizing. This mediating role of both reward sensitivity and cognitive abilities was focusing on the behavioral/externalizing and neurodevelopmental dimensions of psychopathology.

Conclusion

We provide a better understanding of how genetic risks for MDD and ADHD confer risks for psychopathology and suggest potential prevention/intervention targets for children at-risk.
An Assessment of Bayesian Model-Averaged Logistic Regression for Intensive-Care Prognosis
Authors: Dybowski Richard
Published: June 2020

Logistic regression is the standard method for developing prognostic models for intensive care, but this approach does not take into account the uncertainty in the model selected and the uncertainty in its regression coefficients. This weakness can be addressed by adopting a Bayesian model-averaged approach to logistic regression; however, with respect to the dataset used for our study, we found maximum likelihood to be as effective as the more elaborate Bayesian approach, and an implementation of model averaging did not improve performance. Nevertheless, the Bayesian approach has the theoretical advantage that it can exploit prior knowledge about regression coefficient and model probabilities.
An Aberration Detection-Based Approach for Sentinel Syndromic Surveillance of COVID-19 and Other Novel Influenza-Like Illnesses
Authors: Wen Andrew , Wang Liwei , He Huan , Liu Sijia , Fu Sunyang , Sohn Sunghwan , Kugel Jacob A. , Kaggal Vinod C. , Huang Ming , Wang Yanshan , Shen Feichen , Fan Jungwei , Liu Hongfang
Published: June 2020

Coronavirus Disease 2019 (COVID-19) has emerged as a significant global concern, triggering harsh public health restrictions in a successful bid to curb its exponential growth. As discussion shifts towards relaxation of these restrictions, there is significant concern of second-wave resurgence. The key to managing these outbreaks is early detection and intervention, and yet there is significant lag time associated with usage of laboratory confirmed cases for surveillance purposes. To address this, syndromic surveillance can be considered to provide a timelier alternative for first-line screening. Existing syndromic surveillance solutions are however typically focused around a known disease and have limited capability to distinguish between outbreaks of individual diseases sharing similar syndromes. This poses a challenge for surveillance of COVID-19 as its active periods are tend to overlap temporally with other influenza-like illnesses. In this study we explore performing sentinel syndromic surveillance for COVID-19 and other influenza-like illnesses using a deep learning-based approach. Our methods are based on aberration detection utilizing autoencoders that leverages symptom prevalence distributions to distinguish outbreaks of two ongoing diseases that share similar syndromes, even if they occur concurrently. We first demonstrate that this approach works for detection of outbreaks of influenza, which has known temporal boundaries. We then demonstrate that the autoencoder can be trained to not alert on known and well-managed influenza-like illnesses such as the common cold and influenza. Finally, we applied our approach to 2019-2020 data in the context of a COVID-19 syndromic surveillance task to demonstrate how implementation of such a system could have provided early warning of an outbreak of a novel influenza-like illness that did not match the symptom prevalence profile of influenza and other known influenza-like illnesses.
Evidence for ethnic inequalities in mortality related to COVID-19 infections: Findings from an ecological analysis of England and Wales
Authors: Nazroo James , Bécares Laia
Published: June 2020

Background

In the absence of direct data on ethnic inequalities in COVID-19 related mortality in the UK, we examine the relationship between ethnic composition of an area and rate of mortality in the area.

Methods

Ecological analysis using COVID-19 related mortality rates occurring by 24thApril 2020, and ethnic composition of the population, across local authorities in England and Wales. Account is taken of age, population density, area deprivation and pollution.

Results

For every 1% rise in proportion of the population who are ethnic minority, COVID-19 related deaths increased by 5·10 (3·99 to 6·21) per million. This rise is present for each ethnic minority category examined. The size of this increase is a little reduced in a fully adjusted model, suggesting that some of the association results from ethnic minority people living in more densely populated, more polluted and more deprived areas.

This estimate suggests that the average England and Wales COVID-19 related death rate would rise by 25% in a local authority with twice the average number of ethnic minority people.

Discussion

We find clear evidence that rates of COVID-19 related mortality within a local authority increase as the proportion of the population who are ethnic minority increases. We suggest that this is a consequence of social and economic inequalities, including among key workers, driven by entrenched structural and institutional racism and racial discrimination. We argue that these factors should be central to any investigation of ethnic inequalities in COVID-19 outcomes.