bluuebunny/crossref_metadata_2025 huggingface dataset:
Where have all the spiders gone? Observations of a dramatic population density decline in the once very abundant garden spider,Araneus diadematus(Araneae: Araneidae), in the Swiss midland
Authors: Nyffeler Martin , Bonte Dries
Published: March 2020

Aerial web-spinning spiders (including large orb-weavers) depend, as a group of insectivores, completely on flying insects as a food source. The recent widespread loss of flying insects across large parts of western Europe, both in terms of diversity and biomass, can therefore be anticipated to have a drastic negative impact on survival and abundance of this type of spiders. To test the putative importance of such a to date neglected trophic cascade, a survey of population densities of the European garden spiderAraneus diadematus– a large orb-weaving spider – was conducted in late summer 2019 on twenty sites of the Swiss midland. The data from this survey were compared with published population densities for this species from the previous century. The study verifies above-mentioned hypothesis that this spider’s present-day overall mean population density has declined alarmly to densities much lower than can be expected from normal population fluctuations (0.7% of the historical densities). Review of other available records suggests this pattern is widespread and not restricted to this region. In conclusion, the here documented abundance decline of this once so abundant spider in the Swiss midland is evidently revealing a bottom-up trophic cascade in response to the widespread loss of flying insect prey in recent decades.
Case fatality risk of novel coronavirus diseases 2019 in China
Authors: Deng Xiaowei , Yang Juan , Wang Wei , Wang Xiling , Zhou Jiaxin , Chen Zhiyuan , Li Jing , Chen Yinzi , Yan Han , Zhang Juanjuan , Zhang Yongli , Wang Yan , Qiu Qi , Gong Hui , Wei Xianglin , Wang Lili , Sun Kaiyuan , Wu Peng , Ajelli Marco , Cowling Benjamin J. , Viboud Cecile , Yu Hongjie
Published: March 2020

Objective

The outbreak of novel coronavirus disease 2019 (COVID-19) imposed a substantial health burden in mainland China and remains a global epidemic threat. Our objectives are to assess the case fatality risk (CFR) among COVID-19 patients detected in mainland China, stratified by clinical category and age group.

Methods

We collected individual information on laboratory-confirmed COVID-19 cases from publicly available official sources from December 29, 2019 to February 23, 2020. We explored the risk factors associated with mortality. We used methods accounting for right-censoring and survival analyses to estimate the CFR among detected cases.

Results

Of 12,863 cases reported outside Hubei, we obtained individual records for 9,651 cases, including 62 deaths and 1,449 discharged cases. The deceased were significantly older than discharged cases (median age: 77 vs 39 years, p<0.001). 58% (36/62) were male. Older age (OR 1.18 per year; 95%CI: 1.14 to 1.22), being male (OR 2.02; 95%CI: 1.02 to 4.03), and being treated in less developed economic regions (e.g., West and Northeast vs. East, OR 3.93; 95%CI: 1.74 to 8.85) were mortality risk factors. The estimated CFR was 0.89-1.24% among all cases. The fatality risk among critical patients was 2-fold higher than that among severe and critical patients, and 24-fold higher than that among moderate, severe and critical patients.

Conclusions

Our estimates of CFR based on laboratory-confirmed cases ascertained outside of Hubei suggest that COVID-19 is not as severe as severe acute respiratory syndrome and Middle East respiratory syndrome, but more similar to the mortality risk of 2009 H1N1 influenza pandemic in hospitalized patients. The fatality risk of COVID-19 is higher in males and increases with age. Our study improves the severity assessment of the ongoing epidemic and can inform the COVID-19 outbreak response in China and beyond.
Clinical characteristics of 101 COVID-19 nonsurvivors in Wuhan, China: a retrospective study
Authors: Shi Qiao , Zhao Kailiang , Yu Jia , Jiang Fang , Feng Jiarui , Zhao Kaiping , Zhang Xiaoyi , Chen Xiaoyan , Hu Peng , Hong Yupu , Li Man , Liu Fang , Chen Chen , Wang Weixing
Published: March 2020

Background

The outbreak of COVID-19 has aroused global concerns. We aimed to describe the clinical characteristics of COVID-19 nonsurvivors and analyze possible causes for the rapid disease progress to death.

Methods

Patients with confirmed COVID-19 died in Renmin Hospital of Wuhan University before February 15, 2020, were identified. We obtained epidemiological, demographic, and clinical data from electronic medical records.

Results

Among 101 nonsurvivors, the median age was 71.0 years (IQR, 59.0-80.0), 59.4% were male, 79.2% had one or more comorbidities including hypertension (58.4%), cardiovascular disease (22.8%), diabetes (20.8%) etc. The most common symptoms were fever (76.2%), cough (58.4%) and dyspnea (54.5%). Respiratory failure (99.0%), acute cardiac injury (52.5%), sepsis (40.6%) and acute kidney injury (23.8%) were most common complications. Compared with patients died after 3 days of admission, patients died within 3 days of admission had significantly higher white blood cell count (10.8 vs 6.7×109/L, P=0.001) and neutrophil count (8.9 vs 5.5×109/L, P=0.001), longer prothrombin time (13.2 vs 12.5 s, P=0.040), higher D-dimer concentration (7.64 vs 2.82, P=0.040), higher lactate level (2.9 vs 2.2 mmol/L, P=0.042), lower oxygen saturation (85.0% vs 91.0%, P=0.008), and were more likely to suffer sepsis (52.1% vs 30.2%, P=0.025).

Conclusions

Older patients with underlying comorbidities suffering COVID-19 were at high risk of death. Respiratory failure, acute cardiac injury and acute kidney injury played crucial roles in the death of COVID-19 patients. Early development of sepsis was associated with the rapid disease progress to death.
Genome sequencing combining prenatal ultrasound in the evaluation of fetal CNS structural anomalies
Authors: Yang Ying , Zhao Sheng , Sun Guoqiang , Chen Fang , Zhang Tongda , Song Jieping , Yang Wenzhong , Wang Lin , Zhan Nianji , Yang Xiaohong , Zhu Xia , Rao Bin , Yin Zhenzhen , Zhou Jing , Yan Haisheng , Huang Yushan , Ye Jingyu , Huang Hui , Cheng Chen , Zhu Shida , Guo Jian , Xu Xun , Chen Xinlin
Published: March 2020

Purpose

Genome sequencing (GS) is potentially the most suitable diagnostic tools for fetal CNS structural anomalies. However, its efficacy hasn’t been proved in large cohort of fetal CNS structural anomalies.

Methods

Patients were enrolled by a multiple-level referral system when fetal CNS structure anomalies were found by ultrasonography. Samples from fetuses were subjected to GS.

Results

Data of 162 fetuses with 11 frequent types of CNS anomalies was collected. The overall diagnosis yield of GS was 38.9%. 36(20.3%) fetuses were detected with chromosomal anomalies and pathogenic CNVs. Pathogenic or likely pathogenic single-gene variants and intragenic CNVs were found in 24 and three fetuses, contributing 14.8% and 1.9% diagnostic yield respectively. The diagnostic rate in 41 fetuses with CNS malformation combined with anomalies out of brain was as high as 73.3%. Malformations of the posterior cerebral fossa, abnormal neuronal proliferation and migration have the highest diagnostic rates. NTDs had the second lowest diagnostic rates of 14.7% and none pathogenic variants were found in ultrasound anomalies that suggested destructive cerebral lesions.

Conclusion

GS is an efficient genetic testing tool with the diagnostic power compared to current CMA plus ES procedure in fetal CNS anomalies evaluation.
Memory reconsolidation impairments in sign-tracking to an audiovisual compound stimulus
Authors: Drame Mohamed L. , Balaet Maria , Lee Jonathan L. C.
Published: March 2020

Studies of memory reconsolidation of pavlovian memories have typically employed unimodal conditioned stimuli, despite the use of multimodal compound stimuli in other settings. Here we studied sign-tracking behaviour to a compound audiovisual stimulus. First, we observed not unexpectedly that sign-tracking was poorer to the audiovisual compound than to unimodal visual stimuli. Then, we showed that, depending on the parameters of compound stimulus re-exposure at memory reactivation, systemic MK-801 treatment either impaired extinction to improve signtracking at test, or disrupted reconsolidation to impair test behaviour. When memory reactivation consisted of re-exposure to only the auditory component of the compound stimulus, we observed sign-tracking impairments following MK-801 treatment, but only under certain test conditions. This was in contrast to the consistent impairment following reactivation with the full audiovisual compound. Moreover, the parameters of auditory stimulus presentation to enable MK-801-induced impairment at test varied depending on whether the stimulus was presented within or outside the training context. These findings suggest that behaviour under the control of appetitive pavlovian compound stimuli can be modulated by targeting both extinction and reconsolidation, and that it is not necessary to re-expose to the full compound stimulus in order to achieve a degree of modulation of behaviour.
Incorporating Prior Knowledge into Regularized Regression
Authors: Zeng Chubing , Thomas Duncan Campbell , Lewinger Juan Pablo
Published: March 2020

Motivation

Associated with genomic features like gene expression, methylation, and genotypes, used in statistical modeling of health outcomes, there is a rich set of meta-features like functional annotations, pathway information, and knowledge from previous studies, that can be used post-hoc to facilitate the interpretation of a model. However, using this meta-feature information a-priori rather than post-hoc can yield improved prediction performance as well as enhanced model interpretation.

Results

We propose a new penalized regression approach that allows a-priori integration of external meta-features. The method extends LASSO regression by incorporating individualized penalty parameters for each regression coefficient. The penalty parameters are in turn modeled as a log-linear function of the meta-features and are estimated from the data using an approximate empirical Bayes approach. Optimization of the marginal likelihood on which the empirical Bayes estimation is based is performed using a fast and stable majorization-minimization procedure. Through simulations, we show that the proposed regression with individualized penalties can outperform the standard LASSO in terms of both parameters estimation and prediction performance when the external data is informative. We further demonstrate our approach with applications to gene expression studies of bone density and breast cancer.

Availability and implementation

The methods have been implemented in the R packagextunefreely available for download from CRAN.
A codon model for associating phenotypic traits with altered selective patterns of sequence evolution
Authors: Halabi Keren , Karin Eli Levy , Guéguen Laurent , Mayrose Itay
Published: March 2020

Changes in complex phenotypes, such as pathogenicity levels, trophic lifestyle, and habitat shifts are brought on by multiple genomic changes: sub- and neofunctionalization, loss of function, and levels of gene expression. Thus, detecting the signature of selection in coding sequences and associating it with shifts in phenotypic state can unveil the genes underlying complex traits. Phylogenetic branch-site codon models are routinely applied to detect changes in selective patterns along specific branches of the phylogeny. These methods rely on a pre-specified partition of the phylogeny to branch categories, thus treating the course of trait evolution as fully resolved and assuming that transitions in phenotypic states have occurred only at speciation events. Here we present TraitRELAX, a new phylogenetic model that alleviates these strong assumptions by explicitly accounting for the uncertainty in the evolution of both trait and coding sequences. This joint statistical framework enables the detection of changes in selection intensity upon repeated trait transitions. We evaluated the performance of TraitRELAX using simulations and then applied it to two case studies. Using TraitRELAX, we found an intensification of selection in the SEMG2 gene in polygynandrous species of primates compared to species of other mating forms, as well as changes in the intensity of purifying selection operating on sixteen bacterial genes upon transitioning from free-living to an endosymbiotic lifestyle.
Evidence supporting an antimicrobial origin of targeting peptides to endosymbiotic organelles
Authors: Garrido Clotilde , Caspari Oliver D. , Choquet Yves , Wollman Francis-André , Lafontaine Ingrid
Published: March 2020

Mitochondria and chloroplasts emerged from primary endosymbiosis. Most proteins of the endosymbiont were subsequently expressed in the nucleo-cytosol of the host and organelle-targeted via the acquisition of N-terminal presequences, whose evolutionary origin remains enigmatic. Using a quantitative assessment of their physico-chemical properties, we show that organelle targeting peptides, which are distinct from signal peptides targeting other subcellular compartments, group with a subset of antimicrobial peptides. We demonstrate that extant antimicrobial peptides target a fluorescent reporter to either the mitochondria or the chloroplast in the green algaChlamydomonas reinhardtiiand, conversely, that extant targeting peptides still display antimicrobial activity. Thus, we provide strong computational and functional evidence for an evolutionary link between organelle-targeting and antimicrobial peptides. Our results support the view that resistance of bacterial progenitors of organelles to the attack of host antimicrobial peptides has been instrumental in eukaryogenesis and in emergence of photosynthetic eukaryotes.
IgG-aggregates rapidly up-regulate FcgRI expression at the surface of human neutrophils in a FcgRII-dependent fashion: A crucial role for FcgRI in the generation of reactive oxygen species
Authors: Huot Sandrine , Laflamme Cynthia , Fortin Paul R. , Boilard Eric , Pouliot Marc
Published: March 2020

Autoimmune complexes are an important feature of several autoimmune diseases such as lupus, as they contribute to tissue damage through the activation of immune cells. Neutrophils, key players in lupus, interact with immune complexes through Fc gamma receptors (FcgR). Incubation of neutrophils with aggregated-IgGs caused degranulation and increased the surface expression of FcgRI within minutes in a concentration-dependent fashion. After 30 min, IgG aggregates (1 mg/ml) up-regulated FcgRI by 4.95 ± 0.45-fold. FcgRI-positive neutrophils reached 67.24% ± 6.88% on HA-IgGs stimulated neutrophils, from 3.12% ± 1.62% in non-stimulated cells, ranking IgG-aggregates among the most potent known agonists. FcgRIIa, and possibly FcgRIIIa, appeared to mediate this up-regulation. Also, FcgRI-dependent signaling proved necessary for reactive oxygen species (ROS) production in response to IgG-aggregates. Finally, combinations of bacterial materials with aggregates dramatically boosted ROS production. This work suggests FcgRI as an essential component in the response of human neutrophils to immune complexes leading to the production of ROS, which may help explain how neutrophils contribute to tissue damage associated with immune complex-associated diseases, such as lupus.
Cystathionine β-synthase deficiency impairs vision in the fruit fly,Drosophila melanogaster
Authors: Flores-Flores Marycruz , Moreno-García Leonardo , Ángeles Castro-Martínez Felipe , Nahmad Marcos
Published: March 2020

Purpose

In humans, deficiency in Cystathionine β-Synthase (CBS) levels leads to an abnormal accumulation of homocysteine and results in classic homocystinuria, a multi-systemic disorder affecting connective tissue, muscles, the central nervous system and the eyes. However, the genetic and molecular mechanisms underlying vision problems in patients with homocystinuria are little understood.

Materials and Methods

The fruit fly,Drosophila melanogaster, is a useful experimental system to investigate the genetic basis of several human diseases, but no study to date has used Drosophila as model of homocystinuria. Here we use genetic tools to down-regulate CBS and classical behavioral assays to propose Drosophila as a model of homocystinuria to study vision problems.

Results

We present evidence that CBS-deficient flies show an abnormal stereotypical behavior of attraction towards a luminous source or phototaxis, consistent with severe myopia in humans. We show that this behavior cannot be fully attributed to a motor or olfactory deficiency but most likely to an impaired vision. CBS-deficient flies are overall smaller, but smaller eyes do not explain their erratic phototactic response.

Conclusions

We propose Drosophila as a useful model to investigate ocular manifestations underlying homocystinuria.
Interrupting reactivation of immunological memory reprograms allergy and averts anaphylaxis
Authors: Bruton Kelly , Spill Paul , Vohra Shabana , Baribeau Owen , Manzoor Saba , Gadkar Siyon , Davidson Malcolm , Walker Tina D. , Ellenbogen Yosef , Florescu Alexandra , Wen Jianping , Chu Derek K. , Waserman Susan , Jiménez-Saiz Rodrigo , Epelman Slava , Robbins Clinton , Jordana Manel
Published: March 2020

IgE production against innocuous antigens can lead to life-threatening reactions such as anaphylaxis. While IgE levels drastically decline with strict allergen avoidance, the ability to regenerate IgE can persist for a lifetime, as is the case for peanut allergy. The mechanism by which IgE regenerates remains unresolved. A novel culture system and application of single-cell RNA-sequencing, elucidated the transcriptomic signature of human peanut-reactive B and T cells and revealed IL-4/IL-13 as a signaling pathway critical for the IgE recall response. Indeed, interruption of this pathway not only prevented IgE production and anaphylaxis, but also reprogrammed the pathogenic response against peanut. This investigation advances our understanding of the mechanism that regenerates IgE in food allergy and spotlights IL-4/IL-13 blockade as a therapeutic with disease-transforming potential.

One Sentence Summary

Single-cell transcriptomics of allergic memory responses reveals how to teach the immune system to forget.
Marine snow as a habitat for microbial mercury methylators in the Baltic Sea
Authors: Capo Eric , Bravo Andrea Garcia , Soerensen Anne L. , Bertilsson Stefan , Pinhassi Jarone , Feng Caiyan , Andersson Anders F. , Buck Moritz , Björn Erik
Published: March 2020

Methylmercury (MeHg), a neurotoxic compound biomagnifying in aquatic food webs, can be a threat to human health via fish consumption. However, the composition and distribution of the microbial communities mediating the methylation of mercury (Hg) to MeHg in marine systems remain largely unknown. In order to fill this gap of knowledge, we used the Baltic Sea Reference Metagenome (BARM) dataset to study the distribution of the genes involved in Hg methylation (thehgcABgene cluster). We determined the relative abundance of thehgcABgenes and their taxonomic identity in 81 brackish metagenomes that cover spatial, seasonal and redox variability in the Baltic Sea water. ThehgcABgenes were predominantly detected in anoxic water, but somehgcABgenes were also detected in hypoxic and normoxic waters. Higher relative quantities ofhgcABgenes were found in metagenomes from marine snow compared to free-living communities in anoxic water, suggesting that marine snow are hotspot habitats for Hg methylators in oxygen-depleted seawater. Phylogenetic analysis identified well-characterized Hg methylators such as Deltaproteobacteria in oxygen-depleted water, but also uncovered Hg methylators within the Spirochaetes and Lentisphaerae phyla. Altogether, our work unveils the diversity of the microorganisms mediating MeHg production in the Baltic Sea and pinpoint the ecological niches of these microorganisms within the marine water column.
Optimized sgRNA design by deep learning to balance the off-target effects and on-target activity of CRISPR/Cas9
Authors: Lan Jie , Cui Yang , Wang Xiaowen , Song Guangtao , Lou Jizhong
Published: March 2020

The CRISPR/Cas9 system derived from bacteria especiallyStreptococcus pyogenes(SpyCas9) is currently considered as the most advanced tool used for numerous areas of biological study in which it is useful to target or modify specific DNA sequences. However, low on-target cleavage efficiency and off-target effects impede its wide application. Several different sgRNA design tools forSpyCas9 by using various algorithms have been developed, including linear regression model, support vector machine (SVM) model and convolutional neuron network model. While the deep insight into the sgRNA features contributing for both on-target activity and off-target still remains to be determined. Here, with public large-scale CRISPR screen data, we evaluated contribution of different features influence sgRNA activity and off-target effects, and developed models for sgRNA off-target evaluation and on-target activity prediction. In addition, we combined both activity and off-target prediction models and packaged them as an online sgRNA design tool, OPT-sgRNA.
Stress priming affects fungal competition – evidence from a combined experimental and modeling study
Authors: Wesener Felix , Szymczak Aleksandra , Rillig Matthias C. , Tietjen Britta
Published: March 2020

Priming, an inducible stress defense strategy that prepares an organism for an impending stress event, is common in microbes and has been studied mostly in isolated organisms or populations. How the benefits of priming change in the microbial community context and, vice versa, whether priming influences competition between organisms, remains largely unknown. In this combined experimental and modeling study, we developed a cellular automaton model based on dedicated data of different isolates of soil fungi in isolation and pairwise competition experiments. With the model, we simulated growth of the ascomyceteChaetomium elatumcompeting against other fungi to understand which species traits influence the benefit of priming and the effect of priming on competition. We showed that competition changes the priming benefit compared to isolated growth, and that it depends not only on the primeable species itself, but also on the competitors’ traits such as growth rate, primeability and stress susceptibility. In addition, we showed that priming benefits were not always reflected in the competitive outcome. With this study, we transferred insights on priming from studies in isolation to the community context. This is an important step towards understanding the role of inducible defenses in microbial community assembly and composition.
An Integrated Systems Biology Approach Identifies the Proteasome as a Critical Host Machinery for ZIKV and DENV Replication
Authors: Song Guang , Lee Emily M. , Pan Jianbo , Xu Miao , Rho Hee-Sool , Cheng Yichen , Whitt Nadia , Yang Shu , Kouznetsova Jennifer , Klumpp-Thomas Carleen , Michael Samuel G. , Moore Cedric , Yoon Ki-Jun , Christian Kimberly M. , Simeonov Anton , Huang Wenwei , Xia Menghang , Huang Ruili , Lal-Nag Madhu , Tang Hengli , Zheng Wei , Qian Jiang , Song Hongjun , Ming Guo-li , Zhu Heng
Published: March 2020

The Zika (ZIKV) and dengue (DENV) flaviviruses exhibit similar replicative processes but distinct clinical outcomes. A systematic understanding of virus-host protein-protein interaction networks can reveal cellular pathways critical to viral replication and disease pathogenesis. Here we employed three independent systems biology approaches toward this goal. First, protein array analysis of direct interactions between individual ZIKV/DENV viral proteins and 20,240 human proteins revealed multiple conserved cellular pathways and protein complexes, including proteasome complexes. Second, an RNAi screen of 10,415 druggable genes to identify host proteins required for ZIKV infection uncovered proteasome proteins. Third, a high-throughput screening of 6,016 bioactive compounds for ZIKV inhibitors yielded 134 effective compounds, including six proteasome inhibitors that suppress both ZIKV and DENV replication. Integrative analyses of these orthogonal datasets pinpoints proteasome as critical host machinery for ZIKV/DENV replication. Our study provides multi-omics datasets for further studies of flavivirus-host interactions, disease pathogenesis, and new drug targets.
Queuing models of gene expression: Analytical distributions and beyond
Authors: Shi C. , Jiang Y. , Zhou T.
Published: March 2020

Activation of a gene is a multistep biochemical process, involving recruitments of transcription factors and histone kinases as well as modification of histones. Many of these intermediate reaction steps would have been unspecified by experiments. Therefore, classical two-state models of gene expression established based on the memoryless (or Markovian) assumption would not well describe the reality in gene expression. In fact, recent experimental data have indicated that the inactive phases of gene promoters are differently distributed, showing strong memory. Here, we use a non-exponential waiting-time distribution to model the complex activation process of a gene, and analyze a queuing model of stochastic transcription. We successfully derive the analytical expression for the mRNA distribution, which provides insight into the effect of molecular memory created by complex activating events on the mRNA expression. We find that the reduction in the waiting-time noise may result in the increase in the mRNA noise, contrary to the previous conclusion. Based on the derived distribution, we also develop a method to infer the waiting-time distribution from a known mRNA distribution. Data analysis on a realistic example verifies the validity of this method.

SIGNIFICANCE

Activation of a gene is a complex biochemical process and involve several intermediate reaction steps, many of which have been unspecified by experiments. Stochastic models of gene expression that were previously established based on the constant reaction rates would not well reflect the reality in gene expression. To this end, we study a queuing model of stochastic transcription which assume that the reaction waiting time follows a general distribution and derive the analytical expression for mRNA distribution. Our results provide insight into the role of molecular memory in fine-tuning the gene expression noise, and can be used to infer the underlying molecular mechanism.
Converting networks to predictive logic models from perturbation signalling data with CellNOpt
Authors: Gjerga Enio , Trairatphisan Panuwat , Gabor Attila , Koch Hermann , Chevalier Celine , Ceccarelli Francesco , Dugourd Aurelien , Mitsos Alexander , Saez-Rodriguez Julio
Published: March 2020

Motivation

The molecular changes induced by perturbations such as drugs and ligands are highly informative of the intracellular wiring. Our capacity to generate large data-sets is increasing steadily as new experimental approaches are developed. A useful way to extract mechanistic insight from the data is by integrating them with a prior knowledge network of signalling to obtain dynamic models. Logic models scale better with network size than alternative kinetic models, while keeping the interpretation of the model simple, making them particularly suitable for large datasets.

Results

CellNOpt is a collection of Bioconductor R packages for building logic models from perturbation data and prior knowledge of signalling networks. We have recently developed new components and refined the existing ones. These updates include (i) an Integer Linear Programming (ILP) formulation which guarantees efficient optimisation for Boolean models, (ii) a probabilistic logic implementation for semi-quantitative datasets and (iii) the integration of MaBoSS, a stochastic Boolean simulator. Furthermore, we introduce Dynamic-Feeder, a tool to identify missing links not present in the prior knowledge. We have also implemented systematicpost-hocanalyses to highlight the key components and parameters of our models. Finally, we provide an R-Shiny tool to run CellNOpt interactively.

Availability

R-package(s):https://github.com/saezlab/cellnopt

Contact

julio.saez@bioquant.uni-heidelberg.de

Supplementary information

Supplemental Text.
The total and active bacterial community of the chlorolichenCetraria islandicaand its response to long-term warming in sub-Arctic tundra
Authors: Klarenberg Ingeborg J. , Keuschnig Christoph , Warshan Denis , Jónsdóttir Ingibjörg Svala , Vilhelmsson Oddur
Published: March 2020

Lichens are traditionally defined as a symbiosis between a fungus and a green alga and or a cyanobacterium. This idea has been challenged by the discovery of bacterial communities inhabiting the lichen thalli. These bacteria are thought to contribute to the survival of lichens under extreme and changing environmental conditions. How these changing environmental conditions affect the lichen-associated bacterial community composition remains unclear.

We describe the total (rDNA-based) and potentially metabolically active (rRNA-based) bacterial community of the lichenCetaria islandicaand its response to long-term warming using a 20-year warming experiment in an Icelandic sub-Arctic tundra. 16S rRNA and rDNA amplicon sequencing showed that the orders Acetobacterales (of the class Alphaproteobacteria) and Acidobacteriales (of the phylum Acidobacteria) dominated the bacterial community. Numerous ASVs (amplicon sequence variants) taxa could only be detected in the potentially active community but not in the total community. Long-term warming led to increases in relative abundance on class, order and ASV level. Warming altered the relative abundance of ASVs of the most common bacterial genera, such asGranulicellaandEndobacter. The potentially metabolically active bacterial community was also more responsive to warming than the total community.

Our results suggest that the bacterial community of the lichenC. islandicais dominated by acidophilic taxa and harbors disproportionally active rare taxa. We also show for the first time that climate warming can lead to shifts in lichen-associated bacterial community composition.
Queen pheromone modulates the expression of epigenetic modifier genes in the brain of honeybee workers
Authors: Cardoso-Junior Carlos Antônio Mendes , Ronai Isobel , Hartfelder Klaus , Oldroyd Benjamin P.
Published: March 2020

Pheromones are used by many insects to mediate social interactions. In the highly eusocial honeybee (Apis mellifera) queen mandibular pheromone (QMP) is involved in the regulation of reproduction and behaviour of workers. The molecular mechanisms by which QMP acts are largely unknown. Here we investigate how genes responsible for epigenetic modifications to DNA, RNA and histones respond to the presence of QMP. We show that several of these genes are upregulated in the honeybee brain when workers are exposed to QMP. This provides a plausible mechanism by which pheromone signalling may influence gene expression in the brain of honeybee workers. We propose that pheromonal communication systems, such as those used by social insects, evolved to respond to environmental signals by making use of existing epigenomic machineries.
Bacteroides thetaiotaomicron-infecting bacteriophage isolates inform sequence-based host range predictions
Authors: Hryckowian Andrew J. , Merrill Bryan D. , Porter Nathan T. , Van Treuren William , Nelson Eric J. , Garlena Rebecca A. , Russell Daniel A. , Martens Eric C. , Sonnenburg Justin L.
Published: March 2020

Our emerging view of the gut microbiome largely focuses on bacteria and less is known about other microbial components such as of bacteriophages (phages). Though phages are abundant in the gut, very few phages have been isolated from this ecosystem. Here, we report the genomes of 27 phages from the United States and Bangladesh that infect the prevalent human gut bacteriumBacteroides thetaiotaomicron. These phages are mostly distinct from previously sequenced phages with the exception of two, which are crAss-like phages. We compare these isolates to existing human gut metagenomes, revealing similarities to previously inferred phages and additional unexplored phage diversity. Finally, we use host tropisms of these phages to identify alleles of phage structural genes associated with infectivity. This work provides a detailed view of the gut’s “viral dark matter” and a framework for future efforts to further integrate isolation- and sequencing-focused efforts to understand gut-resident phages.
Rapid emergence of clonal interference during malaria parasite cultivation
Authors: Jett Catherine , Dia Aliou , Cheeseman Ian H.
Published: March 2020

Laboratory cultivation of the malaria parasitePlasmodium falciparumhas underpinned nearly all advances in malariology in the past 30 years. When freshly isolated clinical isolates are adapted toin vitroculture mutations rapidly fix increasing the parasite growth rate and stability. While the dynamics of culture adaptation are increasingly well characterized, we know little about the extent of genomic variation that arises and spreads during long term culture. To address this we cloned the 3D7 reference strain and maintained a culture for ~84 asexual cycles (167 days). Growth rate of the culture population increased 1.14-fold over this timeframe. We used single cell genome sequencing of parasites at cycles 21 and 84 to measure the accumulation of diversityin vitro. This parasite population showed strong signals of adaptation across this time frame. By cycle 84 two dominant clades had arisen and were segregating with the dynamics of clonal interference. This highlights the continual process of adaptation in malaria parasites, even in parasites which have been extensively adapted to long term culture.
The anti-tubercular activity of simvastatin is mediated by cholesterol-dependent regulation of autophagy via the AMPK-mTORC1-TFEB axis
Authors: Bruiners Natalie , Dutta Noton K. , Guerrini Valentina , Salamon Hugh , Yamaguchi Ken D. , Karakousis Petros C. , Gennaro Maria L.
Published: March 2020

Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. We investigated the mechanism of anti-tubercular action of simvastatin inMycobacterium tuberculosis-infected human monocytic cells. We found that the anti-tubercular activity of statins was phenocopied by cholesterol-branch but not prenylation-branch inhibitors. Moreover, statin treatment blocked activation of mechanistic target of rapamycin complex 1 (mTORC1), activated AMP-activated protein kinase (AMPK) through increased intracellular AMP:ATP ratios, and favored nuclear translocation of transcription factor EB (TFEB). These mechanisms all induce autophagy, which is anti-mycobacterial. The biological effects of simvastatin on the AMPK-mTORC1-TFEB-autophagy axis were reversed by adding exogenous cholesterol to the cells. Overall, our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, AMPK-mTORC1-TFEB axis, and intracellular infection control, and uncover new anti-tubercular therapy targets.
Molecular mechanism of regulation of the purine salvage enzyme XPRT by the alarmones pppGpp, ppGpp, and pGpp
Authors: Anderson Brent W. , Hao Aili , Satyshur Kenneth A. , Keck James L. , Wang Jue D.
Published: March 2020

The alarmones pppGpp and ppGpp mediate starvation response and maintain purine homeostasis to protect bacterial species. Xanthine phosphoribosyltransferase (XPRT) is a purine salvage enzyme that produces the nucleotide XMP from PRPP and xanthine. Combining structural, biochemical and genetic analyses, we show that pppGpp and ppGpp, as well as a third putative alarmone pGpp, all directly interact with XPRT and inhibit XPRT activity by competing with its substrate PRPP. Structural analysis reveals that ppGpp binds the PRPP binding motif within the XPRT active site. This motif is present in another (p)ppGpp target, the purine salvage enzyme HPRT, suggesting evolutionary conservation in different enzymes. However, XPRT oligomeric interaction is distinct from HPRT in that XPRT forms a symmetric dimer with two (p)ppGpp binding sites at the dimer interface. This results in two distinct regulatory features. First, XPRT cooperatively binds (p)ppGpp with a Hill coefficient of 2. Also, XPRT displays differential regulation by the alarmones as it is potently inhibited by both ppGpp and pGpp, but only modestly by pppGpp. Lastly, we demonstrate that the alarmones are necessary for protecting GTP homeostasis against excess environmental xanthine inBacillus subtilis, suggesting that regulation of XPRT is key for regulating the purine salvage pathway.
Nrf2 represses ER stress-related ferroptosis in renal carcinoma cells via HO-1
Authors: Shen Yuanqing , Hu Zhiquan , Tian Jihua , Gan Jiahua , Ke Chunjin , Yang Chunguang , Zeng Xing , Shen Guanxin
Published: March 2020

Selective-induction of regulated cell death is considered as a useful strategy for developing effective therapies against renal cell carcinoma (RCC). In this study, the role of nuclear factor-E2-related factor 2 (Nrf2) and its downstream genes in erastin-induced ferroptosis of renal carcinoma cells was investigated. Erastin induced endoplasmic reticulum (ER) stress and ferroptosis in renal carcinoma cells (786-0 and Caki-1), which was confirmed by morphological changes, increased lipid oxidation and ferroptosis inhibition. Data obtained from TCGA dataset showed that Nrf2 and heme oxygenase-1 (HO-1) were not only significantly differentially expressed between RCC and normal samples, but also associated with better survival in RCC patients. Moreover, the process of ferroptosis induced by erastin in renal carcinoma cells was accompanied by increased expression of Nrf2 and HO-1. Inhibition of Nrf2 or HO-1 expression enhanced lipid ROS accumulation and ferroptosis. Furthermore, pharmacological activation of HO-1 reversed ferroptosis-sensitizing effect of Nrf2 silencing, thereby clarifying the key role of Nrf2/HO-1 pathway in erastin-induced ferroptosis in renal carcinoma cells. In summary, we identified the role of Nrf2/HO-1 signaling pathway in the protection of renal carcinoma cells from ER stress-related ferroptosis, which indicated that targeting of Nrf2/HO-1 pathway as a viable treatment strategy for RCC.

Abstract Figure

Graphical abstract (supplementary figure):

Nrf2 protects against ER stress-related ferroptosis via HO-1 in renal cancer cells. Cystine/glutamate antiporter (SLC7A11) abbreviated as xCT. Mitochondria abbreviated as Mito.
Predicting the Environmental Suitability and Population at Risk of Podoconiosis in Africa
Authors: Deribe Kebede , Simpson Hope , Pullan Rachel L. , Bosco Mbonigaba Jean , Wanji Samuel , Weaver Nicole Davis , Murray Christopher J. L. , Newport Melanie J. , Hay Simon I. , Davey Gail , Cano Jorge
Published: March 2020

Background

Podoconiosis is a type of tropical lymphedema that causes massive swelling of the lower limbs. The disease is associated with both economic insecurity, due to long-term morbidity-related loss of productivity, and intense social stigma. The geographical distribution and burden of podoconiosis in Africa is uncertain.

Methods

We applied statistical modelling to the most comprehensive database compiled to date to predict the environmental suitability of podoconiosis in the African continent. By combining climate and environmental data and overlaying population figures, we predicted the suitability and human population at risk.

Results

In Africa, environmental suitability for podoconiosis was predicted in 29 countries. By 2020, the total population in areas suitable for podoconiosis was estimated at 114.5 million people, (95% confidence interval: 109.4-123.9) with 16.9 million in areas suitable for both lymphatic filariasis and podoconiosis. Of the total 5,712 implementation units defined by WHO in Africa, 1,655 (29.0%) were found to be environmentally suitable for podoconiosis. The majority of IUs with high environmental suitability are located in Angola (80 IUs), Cameroon (170 IUs), the DRC (244 IUs), Ethiopia (495 IUs), Kenya (217 IUs), Uganda (116 IUs) and Tanzania (112 IUs). Of the 1,655 environmental suitable IUs, 960 (58.0%) require more detailed community-level mapping

Conclusions

Our estimates provide key evidence of the population at risk and geographical extent of podoconiosis in Africa, which will help decision-makers to better plan more integrated intervention programmes.
Topographic Heterogeneity of Lung Microbiota in End-Stage Idiopathic Pulmonary Fibrosis: The Microbiome in Lung Explants-2 (MiLEs-2) Study
Authors: Valenzi Eleanor B , Yang Haopu , Sembrat John C , Yang Libing , Winters Spencer , Nettles Rachel , Kass Daniel J , Qin Shulin , Wang Xiaohong , Myerburg Michael M , Methé Barbara , Fitch Adam , Alder Jonathan K , Benos Panayiotis V , McVerry Bryan J , Rojas Mauricio , Morris Alison , Kitsios Georgios D
Published: March 2020

Background

Lung microbiota profiles in patients with early idiopathic pulmonary fibrosis (IPF) have been associated with disease progression; however, the topographic heterogeneity of lung microbiota and their roles in advanced IPF are unknown.

Methods

We sampled subpleural tissue from up to three lobes as well as airway-based specimens (bronchial washings and airway tissue) in patients with IPF, connective tissue disease-associated interstitial lung disease (CTD-ILD), cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD) and donor lungs deemed unsuitable for transplant (controls). We quantified bacterial load and profiled communities by polymerase chain reaction (PCR) amplification and sequencing of the 16S rRNA gene.

Findings

Explants from 62 IPF, 15 CTD-ILD, 20 CF, 20 COPD and 20 control patients were included. Airway-based samples had higher bacterial load compared to distal parenchymal tissue across all patient groups. IPF basilar tissue had much lower bacterial load compared to CF and control lungs (p<0.001). Among patients with IPF, no differences in microbial community profiles were found between parenchymal tissue samples from different lobes. With Dirichlet multinomial models, a cluster of IPF patients (29%) with distinct composition, high bacterial load and low alpha diversity was identified, exhibiting higher odds for acute exacerbation of IPF or death.

Interpretation

IPF explants exhibited low biomass in the distal parenchyma of all three lobes with higher bacterial load in the airways. The discovery of a distinct subgroup of IPF patients with higher bacterial load and worse clinical outcomes supports investigation of personalized medicine approaches for microbiome-targeted interventions.

Key Messages

What is the key question?

Bronchoalveolar lavage microbiome profiles in early idiopathic pulmonary fibrosis (IPF) have been associated with disease progression, but the regional heterogeneity of resident microbiota in end-stage IPF has not been defined.

What is the bottom line?

IPF explants demonstrate higher bacterial load in airway compared to parenchymal samples, but no differences in between apical or basilar parenchymal samples. A subgroup of patients with higher bacterial load and respiratory pathogen abundance was associated with worse clinical outcomes.

Why read on?

Patient-specific heterogeneity in the lung microbiome of IPF supports the need for personalized microbiome-targeted interventions in IPF.
Prediction of Venous Thromboembolism Based on Clinical and Genetic Factors
Authors: Kolin David A. , Kulm Scott , Elemento Olivier
Published: March 2020

BACKGROUND

Both clinical and genetic factors drive the risk of venous thromboembolism. However, whether clinically recorded risk factors and genetic variants can be combined into a clinically applicable predictive score remains unknown.

METHODS

Using Cox proportional-hazard models, we analyzed the association of risk factors with the likelihood of venous thromboembolism in U.K. Biobank, a large prospective cohort. We created a novel ten point clinical score using seven established clinical risk factors for venous thromboembolism. We also generated a polygenic risk score of 21 single nucleotide polymorphisms to quantify genetic risk. The genetic score was categorized into high risk (top two deciles of scores), intermediate risk (deciles three to eight), and low risk (lowest two deciles). The discrete clinical score led to the following approximate decile categorizations: high risk (5 to 10 points), intermediate risk (3 to 4 points), and low risk (0 to 2 points).

RESULTS

Amongst the 502,536 participants in the U.K. Biobank, there were 4,843 events of venous thromboembolism. Analyses of established clinical risk factors and the most commonly used medications revealed that participants were at decreased risk of venous thromboembolism if they had ever used oral contraceptive pills (hazard ratio, 0.88; 95% confidence interval [CI], 0.79 to 0.99) or if they currently used bendroflumethiazide (hazard ratio, 0.84; 95% CI, 0.74 to 0.95), cod liver oil capsules (hazard ratio, 0.87; 95% CI, 0.77 to 0.99), or atenolol (hazard ratio, 0.79; 95% CI, 0.68 to 0.91). Participants were at significantly increased risk of venous thromboembolism if they were at high clinical risk (hazard ratio, 5.98; 95% CI, 5.43 to 6.59) or high genetic risk (hazard ratio, 2.28; 95% CI, 2.07 to 2.51) relative to participants at low clinical or genetic risk, respectively. Combining clinical risk factors with genetic risk factors produced a model that better predicted risk of venous thromboembolism than either model alone (P<0.001). Participants at high clinical and genetic risk in the combined score had over an eightfold increased risk of venous thromboembolism relative to participants at low risk (hazard ratio, 8.27; 95% CI 7.59 to 9.00).

CONCLUSIONS

By assessing venous thromboembolic events in over 500,000 participants, we identified several known and novel associations between risk factors and venous thromboembolism. Participants in the high risk group of a combined score, consisting of clinical and genetic factors, were over eight times more likely to experience venous thromboembolism than participants in the low risk group.
Extensive single-cell genomics reveals bacterial diversity and diverse phage host ranges in the area in and around the Red Sea
Authors: Nishikawa Yohei , Kogawa Masato , Hosokawa Masahito , Wagatsuma Ryota , Mineta Katsuhiko , Takahashi Kai , Ide Keigo , Yura Kei , Behzad Hayedeh , Gojobori Takashi , Takeyama Haruko
Published: March 2020

To improve our understanding of the environmental microbiome, we developed a single-cell genome sequencing platform, named SAG-gel, which utilizes gel beads for single-cell isolation, cell lysis, and whole genome amplification (WGA) for sequencing. SAG-gel enables serial, parallel and independent reactions of > 100,000 single cells in a single tube, delivering high-quality genome recovery with storable randomized single-cell genome libraries. From soil and marine environmental sources, we acquired 734 partial genomes that are recapitulated in 231 species, 35% of which were assigned as high-to-medium qualities. We found that each genome to be almost unique and 98.7% of them were newly identified, implying the complex genetic diversities across 44 phyla. The various metabolic capabilities including virulence factors and biosynthetic gene clusters were found across the lineages at single-cell resolution. This technology will accelerate the accumulation of reference genomes of uncharacterized environmental microbes and provide us new insights for their roles.