bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of regulatory networks associated with anti-HIV/AIDS genes via integrated transcriptome, epigenome and proteome analyses
Authors: Liu Gexin , Zhang Chunlin , Shi Lei , Zhu Zhenglin
Published: March 2021

There are individuals naturally resistant to HIV. To identify anti-HIV genes and regulatory networks that enable the native ability to resist HIV, we reanalyzed the transcriptome of HIV resistant and susceptible individuals based on previous efforts, and performed regulatory network prediction using HIV-infection related DNA methylation, miRNA and Chip-SEQ data. We totally found 25 potential anti-HIV genes and 23 of them are newly identified. They are enriched in pathways of immunity, neurological system and cell signaling. 4 anti-HIV genes show DNA hypermethylation signatures and 4 are possibly bounded by the HIV-1 Trans-Activator of Transcription protein (Tat). We found a potential HIV-resistance correlated miRNA hsa-miR-3074-5p possibly regulating an anti-HIV hub gene JUN. Our findings provide novel insights for AIDS treatments and approaches to HIV vaccine design.
Ion transport modulators differentially modulate inflammatory responses in THP-1 derived macrophages
Authors: Mitini-Nkhoma Steven C. , Fernando Narmada , Ishaka G.K.D. , Handunnetti Shiroma M. , Pathirana Sisira L.
Published: March 2021

Ion transport modulators are most commonly used to treat various non-communicable diseases including diabetes and hypertension. They are also known to bind to receptors on various immune cells, but the immunomodulatory properties of most ion transport modulators have not been fully elucidated. We assessed the effects of thirteen FDA approved ion transport modulators namely ambroxol HCl, amiloride HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide, metformin, omeprazole, pantoprazole, phenytoin, verapamil, drug X and drug Y on superoxide production, nitric oxide production and cytokine expression by THP-1 derived macrophages that had been stimulated with ethanol-inactivatedMycobacterium bovisBCG. Ambroxol HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide, metformin, pantoprazole, phenytoin, verapamil and drug Y had an inhibitory effect on nitric oxide production, while all the test drugs had an inhibitory effect on superoxide production. Amiloride HCl, diazoxide, digoxin, furosemide, phenytoin, verapamil, drug X and drug Y enhanced the expression of IL-1β and TNF-α. Unlike most immunomodulatory compounds currently in clinical use, most of the test drugs inhibited some inflammatory processes while promoting others. Ion pumps and ion channels could therefore serve as targets for more selective immunomodulatory agents which do not cause overt immunosupression.
Protein allocation and utilization in the versatile chemolithoautotrophCupriavidus necator
Authors: Jahn Michael , Crang Nick , Janasch Markus , Hober Andreas , Forsström Björn , Kimler Kyle , Mattausch Alexander , Chen Qi , Asplund-Samuelsson Johannes , Hudson Elton P.
Published: March 2021

Bacteria must balance the different needs for substrate assimilation, growth functions, and resilience in order to thrive in their environment. Of all cellular macromolecules, the bacterial proteome is by far the most important resource and its size is limited. Here, we investigated how the highly versatile ‘knallgas’ bacteriumCupriavidus necatorreallocates protein resources when grown on different limiting substrates and with different growth rates. We determined protein quantity by mass spectrometry and estimated enzyme utilization by resource balance analysis modeling. We found thatC. necatorinvests a large fraction of its proteome in functions that are hardly utilized. Of the enzymes that are utilized, many are present in excess abundance. One prominent example is the strong expression of CBB cycle genes such as Rubisco during growth on fructose. Modeling and mutant competition experiments suggest that CO2-reassimilation through Rubisco does not provide a fitness benefit for heterotrophic growth, but is rather an investment in readiness for autotrophy.

Highlights

A large fraction of theC. necatorproteome is not utilized and not essential

Highly utilized enzymes are more abundant and less variable

Autotrophy related enzymes are largely underutilized

Re-assimilation of CO2viathe CBB cycle is unlikely to provide a fitness benefit
Stochasticity-induced stabilization weakens in diverse communities
Authors: Pande Jayant , Shnerb Nadav M.
Published: March 2021

Environmental stochasticity and the temporal variations of demographic rates associated with it are ubiquitous in nature. The ability of these fluctuations to stabilize a coexistence state of competing populations (sometimes known as the storage effect) is a counterintuitive feature that has aroused much interest. Here we consider the performance of environmental stochasticity as a stabilizer in diverse communities. We review the results of previous studies which suggest that the stabilizing effects of stochasticity weaken as the number of species increases, provide a systematic numerical exploration of the phenomenon and identify the relevant parameter regimes. Of particular importance is the ratio between the dwell time of the environment and the generation time: we show that stochasticity promotes diversity only when this ratio is smaller than the inverse of the fundamental biodiversity parameter. In an opposite regime, when stochasticity impedes coexistence and lowers the species richness, its effect is determined by the ratio between the strength of environmental variations and the rate at which new types are added to the community via speciation, mutation or immigration.
Predicting Hosts Based on Early SARS-CoV-2 Samples and Analyzing Later World-wide Pandemic in 2020
Authors: Guo Qian , Li Mo , Wang Chunhui , Guo Jinyuan , Jiang Xiaoqing , Tan Jie , Wu Shufang , Wang Peihong , Xiao Tingting , Zhou Man , Fang Zhencheng , Xiao Yonghong , Zhu Huaiqiu
Published: March 2021

The SARS-CoV-2 pandemic has raised the concern for identifying hosts of the virus since the early-stage outbreak. To address this problem, we proposed a deep learning method, DeepHoF, based on extracting the viral genomic features automatically, to predict host likelihood scores on five host types, including plant, germ, invertebrate, non-human vertebrate and human, for novel viruses. DeepHoF made up for the lack of an accurate tool applicable to any novel virus and overcame the limitation of the sequence similarity-based methods, reaching a satisfactory AUC of 0.987 on the five-classification. Additionally, to fill the gap in the efficient inference of host species for SARS-CoV-2 using existed tools, we conducted a deep analysis on the host likelihood profile calculated by DeepHoF. Using the isolates sequenced in the earliest stage of COVID-19, we inferred minks, bats, dogs and cats were potential hosts of SARS-CoV-2, while minks might be one of the most noteworthy hosts. Several genes of SARS-CoV-2 demonstrated their significance in determining the host range. Furthermore, the large-scale genome analysis, based on DeepHoF’s computation for the later world-wide pandemic in 2020, disclosed the uniformity of host range among SARS-CoV-2 samples and the strong association of SARS-CoV-2 between humans and minks.
LowerVibriospp. abundances inZostera marinaleaf canopies suggest a novel ecosystem function for temperate seagrass beds
Authors: Reusch Thorsten B.H. , Schubert Philipp R. , Marten Silke-Mareike , Gill Diana , Karez Rolf , Busch Kathrin , Hentschel Ute
Published: March 2021

Seagrasses, a polyphyletic group of about 60 marine angiosperm species, are the foundation of diverse and functionally important marine habitats along sheltered sedimentary coasts. As a novel ecological function with high societal relevance, a role of the leaf canopy for reducing potentially harmful bacteria has recently been hypothesized. Accordingly, we tested whether or not the abundance of general bacteria and more specifically, those belonging to the genusVibriowere reduced within temperateZostera marina(eelgrass) meadows compared to adjacent sand flats and sampled 5 sites in the south-western Baltic Sea using SCUBA. Compared to non-vegetated area, we found an average reduction of 39% for allVibrioand 63% for the potentially harmfulV. vulnificus/choleraesubtype based on robust plate counting data onVibrioselective agar. The underlying mechanism is currently elusive and clearly merits further study. Our results underline the critical importance of seagrasses in maintaining shallow water ecosystem functioning including water quality and provide further motivation for their protection and restoration.
Polycomb repressive complex 2 coordinates with Sin3 histone deacetylase complex to epigenetically reprogram genome-wide expression ofeffectorsand regulate pathogenicity inMagnaporthe oryzae
Authors: Wu Zhongling , Qiu Jiehua , Shi Huanbin , Lin Chuyu , Yue Jiangnan , Liu Zhiquan , Xie Wei , Kou Yanjun , Tao Zeng
Published: March 2021

The strict suppression and reprogramming of gene expression are necessary at different development stages and/or in response to environment stimuli in eukaryotes. In RiceMagnaporthe oryzaepathosystem,effectorsfrom pathogen are kept transcriptionally silenced in the vegetative growth stage and are highly expressed during invasive growth stage to adapt to the host environment. However, the mechanism of how sucheffectorsare stably repressed in the vegetative stage and its roles during rice blast infection remain unclear so far. Here, we showed that all subunits of Polycomb Repressive Complex 2 are required for such repression by direct H3K27me3 occupancy and pathogenic process inM. oryzae. Suppression of polycomb-mediated H3K27me3 causes an improper induction ofeffectorsduring vegetative growth thus simulating a host environment. Notably, the addition subunit P55 not only acts as the bridge to connect with core subunits to form a complex inM. oryzae, but also recruits Sin3 histone deacetylase complex to prompt H3K27me3 occupancy for stable maintenance of transcriptional silencing of the target genes in the absence of PRC1. In contrast, during invasive growth stage, the repressed state ofeffectorschromatin can be partially erased during pathogenic development resulting in transcriptional activation of effectors therein. Overall, Polycomb repressive complex 2 coordinates with Sin3 histone deacetylase complex to epigenetically reprogram genome-wide expression ofeffectors,which act as molecular switch to memorize the host environment from vegetative to invasive growth, thus contributing to the infection of rice blast.
Integrative genome-scale metabolic modeling reveals versatile metabolic strategies for methane utilization inMethylomicrobium albumBG8
Authors: Villada Juan C. , Duran Maria F. , Kent Lim Chee , Stein Lisa Y. , Lee Patrick K. H.
Published: March 2021

Methylomicrobium albumBG8 is an aerobic methanotrophic bacterium that can mitigate environmental methane emission, and is a promising microbial cell factory for the conversion of methane to value-added chemicals. However, the lack of a genome-scale metabolic model (GEM) ofM. albumBG8 has hindered the development of systems biology and metabolic engineering of this methanotroph. To fill this gap, a high-quality GEM was constructed to facilitate a system-level understanding on the biochemistry ofM. albumBG8. Next, experimental time-series growth and exometabolomics data were integrated into the model to generate context-specific GEMs. Flux balance analysis (FBA) constrained with experimental data derived from varying levels of methane, oxygen, and biomass were used to model the metabolism ofM. albumBG8 and investigate the metabolic states that promote the production of biomass and the excretion of carbon dioxide, formate, and acetate. The experimental and modeling results indicated that the system-level metabolic functions ofM. albumBG8 require a ratio > 1:1 between the oxygen and methane specific uptake rates for optimal growth. Integrative modeling revealed that at a high ratio of oxygen-to-methane uptake flux, carbon dioxide and formate were the preferred excreted compounds; at lower ratios, however, acetate accounted for a larger fraction of the total excreted flux. The results of this study reveal a trade-off between biomass production and organic compound excretion and provide evidence that this trade-off is linked to the ratio between the oxygen and methane specific uptake rates.
Neural networks and extreme gradient boosting predict multiple thresholds and trajectories of microbial biodiversity responses due to browning
Authors: Fontaine Laurent , Khomich Maryia , Andersen Tom , Hessen Dag O. , Rasconi Serena , Davey Marie L. , Eiler Alexander
Published: March 2021

Ecological association studies often assume monotonicity such as between biodiversity and environmental properties although there is growing evidence that non-monotonic relations dominate in nature. Here we apply machine learning algorithms to reveal the non-monotonic association between microbial diversity and an anthropogenic induced large scale change, the browning of freshwaters, along a longitudinal gradient covering 70 boreal lakes in Scandinavia. Measures of bacterial richness and evenness (alpha diversity) showed non-monotonic trends in relation to environmental gradients, peaking at intermediate levels of browning. Depending on the statistical methods, variables indicative for browning could explain 5% of the variance in bacterial community composition (beta diversity) when applying standard methods assuming monotonic relations and up to 45 % with machine learning methods (i.e. extreme gradient boosting and feed-forward neural networks) taking non-monotonicity into account. This non-monotonicity observed at the community level was explained by the complex interchangeable nature of individual taxa responses as shown by a high degree of non-monotonic responses of individual bacterial sequence variants to browning. Furthermore, the non-monotonic models provide the position of thresholds and predict alternative bacterial diversity trajectories in boreal freshwater as a result of ongoing climate and land use changes, which in turn will affect entire ecosystem metabolism and likely greenhouse gas production.
Somewhere I belong: phylogeny and morphological evolution in a species-rich lineage of ectoparasitic flatworms infecting cichlid fishes
Authors: Cruz-Laufer Armando J. , Pariselle Antoine , Jorissen Michiel W. P. , Bukinga Fidel Muterezi , Al Assadi Anwar , Van Steenberge Maarten , Koblmüller Stephan , Sturmbauer Christian , Smeets Karen , Huyse Tine , Artois Tom , Vanhove Maarten P. M.
Published: March 2021

Abstract

A substantial portion of biodiversity evolved through adaptive radiation. However, the effects of explosive speciation on species interactions remain poorly understood. Metazoan parasites infecting radiating host lineages could improve our knowledge because of their intimate host relationships. Yet limited molecular, phenotypic, and ecological data discourage multivariate analyses of evolutionary patterns and encourage the use of discrete characters. Here, we assemble new molecular, morphological, and host range data widely inferred from a species-rich lineage of parasites (Cichlidogyrus, Platyhelminthes: Monogenea) infecting cichlid fishes to address data scarcity. We infer a multi-marker (28S/18S rDNA, ITS1, COI mtDNA) phylogeny of 58/137 species and characterise major lineages through synapomorphies inferred from mapping morphological characters. We predict the phylogenetic position of species without DNA data through shared character states, a combined molecular-morphological phylogenetic analysis, and a classification analysis with support vector machines. Based on these predictions and a cluster analysis, we assess the systematic informativeness of continuous characters, search for continuous equivalents for discrete characters, and suggest new characters for morphological traits not analysed to date. We also model the attachment/reproductive organ and host range evolution using the data of 136/137 described species and multivariate phylogenetic comparative methods (PCMs). We show that discrete characters can mask phylogenetic signals but can be key for characterising species groups. Regarding the attachment organ morphology, a divergent evolutionary regime for at least one lineage was detected and a limited morphological variation indicates host and environmental parameters affecting its evolution. However, moderate success in predicting phylogenetic positions, and a low systematic informativeness and high multicollinearity of morphological characters call for a revaluation of characters included in species characterisations.
Turning movements in real life capture subtle longitudinal and preataxic changes in cerebellar ataxia
Authors: Thierfelder Annika , Seemann Jens , John Natalie , Giese Martin , Schöls Ludger , Timmann Dagmar , Synofzik Matthis , Ilg Winfried
Published: March 2021

OBJECTIVES

Clinical and regulatory acceptance of upcoming molecular treatments in degenerative ataxias might greatly benefit from ecologically valid endpoints which capture change in ataxia severity in patients’ real life. This longitudinal study aimed to unravel quantitative motor biomarkers in degenerative ataxias in real life turning movements which are sensitive for changes both longitudinally and at the preataxic stage.

METHODS

Combined cross-sectional (n=30) and longitudinal (n=14, 1-year interval) observational study in degenerative cerebellar disease (including 8 pre-ataxic mutation carriers) compared to 23 healthy controls. Turning movements were assessed by three body-worn inertial sensors in three conditions: (1) instructed laboratory assessment, (2) supervised free walking, and (3) unsupervised real-life movements.

RESULTS

Measures which quantified dynamic balance during turning – lateral velocity change (LVC) and outward acceleration –, but not general turning measures such as speed, allowed differentiating ataxic against healthy subjects in real life with high effect size (δ=0.68), with LVC also differentiating preataxic against healthy subjects (δ=0.53). LVC was highly correlated with clinical ataxia severity (SARA score, effect size ρ=0.79) and subjective balance confidence (ABC score, ρ=0.66). Moreover, LVC in real life – but not general turning measures, gait measures, or the SARA score – allowed detecting significant longitudinal change in one-year follow-up with high effect size (rprb=0.66).

CONCLUSIONS

Measures of turning allow to capture specific changes of dynamic balance in degenerative ataxia in real life, with high sensitivity to longitudinal differences in ataxia severity and to the preataxic stage. They thus present promising ecologically valid motor biomarkers for capturing change in real life, even in the highly treatment-relevant early stages of degenerative cerebellar disease.
Disease-specific eQTL screening reveals an anti-fibrotic effect of AGXT2 in nonalcoholic fatty liver disease
Authors: Yoo Taekyeong , Joo Sae Kyung , Kim Hyo Jung , Kim Hyun Young , Sim Hyungtai , Lee Jieun , Kim Hee-Hoon , Jung Sunhee , Lee Youngha , Jamialahmadi Oveis , Romeo Stefano , Jeong Won-Il , Hwang Geum-Sook , Kang Keon Wook , Kim Jae Woo , Kim Won , Choi Murim
Published: March 2021

Background & Aims

Nonalcoholic fatty liver disease (NAFLD) poses an impending clinical burden. Genome-wide association studies have revealed a limited contribution of genomic variants to the disease, requiring alternative but robust approaches to identify disease-associated variants and genes. We carried out a disease-specific expression quantitative trait loci (eQTL) screen to identify novel genetic factors that specifically act on NAFLD progression on the basis of genotype.

Methods

We recruited 125 Korean biopsy-proven NAFLD patients and healthy individuals and performed eQTL analyses using 21,272 transcripts and 3,234,941 genotyped and imputed SNPs. We then selected eQTLs that were detected only in the NAFLD group, but not in the control group (i.e., NAFLD-eQTLs). An additional cohort of 162 Korean NAFLD individuals was used for replication. The function of the selected eQTL toward NAFLD development was validated using HepG2, primary hepatocytes and NAFLD mouse models.

Results

The NAFLD-specific eQTL screening yielded 242 loci. Among them,AGXT2, encoding alanine-glyoxylate aminotransferase 2, displayed decreased expression in NAFLD patients homozygous for the non-reference allele of rs2291702, compared to no-NAFLD subjects with the same genotype (P= 4.79 × 10−6). This change was replicated in an additional 162 individuals, yielding a combinedP-value of 8.05 × 10−8from a total of 245 NAFLD patients and 48 controls.

Knockdown ofAGXT2induced palmitate-overloaded hepatocyte death by increasing ER stress, and exacerbated NAFLD diet-induced liver fibrosis in mice. However, overexpression of AGXT2 reversely attenuated liver fibrosis and steatosis as well.

Conclusions

We implicate a new molecular role of AGXT2 in NAFLD. Our overall approach will serve as an efficient tool for uncovering novel genetic factors that contribute to liver steatosis and fibrosis in patients with NAFLD.

Lay summary

Elucidating causal genes for NAFLD has been challenging due to limited tissue availability and the polygenic nature of the disease. Using liver and blood samples from 125 biopsy-proven NAFLD and no-NAFLD Korean individuals and an additional 162 individuals for replication, we devised a new analytic method to identify causal genes. Among the candidates, we found that AGXT2-rs2291702 protects against liver fibrosis in a genotype-dependent manner with the potential for therapeutic interventions. Our approach enables the discovery of NAFLD causal genes that act on the basis of genotype.
A highly accurate model for screening prostate cancer using propensity index panel of ten genes
Authors: Jain Shipra , Malhotra Kawal Preet Kaur , Patiyal Sumeet , Raghava Gajendra P. S.
Published: March 2021

Prostate-specific antigen (PSA) is a key biomarker, which is commonly used to screen patients of prostate cancer. There is a significant number of unnecessary biopsies that are performed every year, due to poor accuracy of PSA based biomarker. In this study, we identified alternate biomarkers based on gene expression that can be used to screen prostate cancer with high accuracy. All models were trained and test on gene expression profile of 500 prostate cancer and 51 normal samples. Numerous feature selection techniques have been used to identify potential biomarkers. These biomarkers have been used to develop various models using different machine learning techniques for predicting samples of prostate cancer. Our logistic regression-based model achieved highest AUROC 0.91 with accuracy 82.42% on validation dataset. We introduced a new approach called propensity index, where expression of gene is converted into propensity. Our propensitybased approach improved the performance of classification models significantly and achieved AUROC 0.99 with accuracy 96.36% on validation dataset. We also identified and ranked selected genes which can be used to discriminate prostate cancer patients from health individuals with high accuracy. It was observed that single gene-based biomarkers can only achieve accuracy around 90%. In this study, we got best performance using a panel of 10 genes; random forest model using propensity index.

Highlights

Application of Machine learning techniques to identify Biomarkers for PRAD cancer.

Highly accurate models developed for classifying prostate cancer vs. normal sample.

Introducing Propensity index concept for enhancing model performance.

Top 10 genes identified using feature selection techniques.
Experimental evolution reveals post-transcriptional regulation as a novel driver ofLeishmaniafitness gain
Authors: Piel Laura , Rajan K. Shanmugha , Bussotti Giovanni , Varet Hugo , Legendre Rachel , Proux Caroline , Douché Thibaut , Giai-Gianetto Quentin , Chaze Thibault , Cokelaer Thomas , Vojtkova Barbora , Gordon-Bar Nadav , Doniger Tirza , Cohen-Chalamish Smadar , Rengaraj Praveenkumar , Besse Céline , Boland Anne , Sadlova Jovana , Deleuze Jean-François , Matondo Mariette , Unger Ron , Volf Petr , Michaeli Shulamit , Pescher Pascale , Späth Gerald F.
Published: March 2021

The protozoan parasiteLeishmania donovanicauses fatal human visceral leishmaniasis in absence of treatment. Genome instability has been recognized as a driver inLeishmaniafitness gain in response to environmental change or chemotherapy. How genome instability generates beneficial phenotypes despite potential deleterious gene dosage effects is unknown. Here we address this important open question applying experimental evolution and integrative systems approaches on parasites adapting toin vitroculture. Phenotypic analyses of parasites from early and late stages of culture adaptation revealed an important fitness tradeoff, with selection for accelerated growth in promastigote culture (fitness gain) impairing infectivity (fitness costs). Comparative genomics, transcriptomics and proteomics analyses revealed a complex regulatory network driving parasite fitness, with genome instability causing highly reproducible, gene dosage-dependent changes in protein abundance linked to post-transcriptional regulation. These in turn were associated with a gene dosage-independent reduction in abundance of flagellar transcripts and a coordinated increase in abundance of coding and non-coding RNAs implicated in ribosomal biogenesis and protein translation. We correlated differential expression of small nucleolar RNAs (snoRNAs) with changes in rRNA modification, providing first evidence thatLeishmaniafitness gain in culture may be controlled by post-transcriptional and epitranscriptomic regulation. Our findings propose a novel model forLeishmaniafitness gain in culture, where differential regulation of mRNA stability and the generation of fitness-adapted ribosomes may potentially filter deleterious from beneficial gene dosage effects and provide proteomic robustness to genetically heterogenous, adapting parasite populations. This model challenges the current, genome-centric approach toLeishmaniaepidemiology and identifies theLeishmaniatranscriptome and non-coding small RNome as potential novel sources for the discovery of biomarkers that may be associated with parasite phenotypic adaptation in clinical settings.
Endosperm turgor pressure both promotes and restricts seed growth and size
Authors: Creff Audrey , Ali Olivier , Bayle Vincent , Ingram Gwyneth , Landrein Benoit
Published: March 2021

Organ size depends on complex biochemical and mechanical interactions between cells and tissues. Here, we investigate the control of seed size, a key agronomic trait, by mechanical interactions between two compartments: the endosperm and the testa. By combining experiments with computational modelling, we tested an incoherent mechanical feedforward loop hypothesis in which pressure-induced stresses play two antagonistic roles; directly driving seed growth, but indirectly inhibiting it through mechanosensitive stiffening of the seed coat. We show that our model can recapitulate wild type growth patterns and explain the small seed phenotype of thehaiku2mutant. Our work further reveals that the developmental regulation of endosperm pressure is needed to prevent a precocious reduction of seed growth rate induced by force-dependent seed coat stiffening.
Prenatal cadmium exposure does not induce greater incidence or earlier onset of autoimmunity in the offspring
Authors: McCall Jamie L. , Blair Harry C. , Blethen Kathryn E. , Hall Casey , Elliott Meenal , Barnett John B.
Published: March 2021

We previously demonstrated that exposure of adult mice to environmental levels of cadmium (Cd) alters the immune cell development and function with increases in anti-streptococcal antibody levels, as well as decreases in splenic natural regulatory T cells (nTreg) in the adult female offspring. Based on these data, we hypothesized that prenatal Cd exposure could predispose an individual to developing autoimmunity as adults. To test this hypothesis, the effects of prenatal Cd on the development of autoimmune diabetes and arthritis were investigated. Non-obese diabetic (NOD) mice were exposed to Cd in a manner identical to our previous studies, and the onset of diabetes was assessed in the offspring. Our results showed a similar time-to-onset and severity of disease to historical data, and there were no statistical differences between Cd-exposed and control offspring. Numerous other immune parameters were measured and none of these parameters showed biologically relevant differences between Cd-exposed and control animals. To test whether prenatal Cd-exposure affected development of autoimmune arthritis, we used SKG mice. While the levels of arthritis were similar between Cd-exposed and control offspring of both sexes, the pathology of arthritis determined by micro-computed tomography (μCT) between Cd-exposed and control animals, showed some statistically different values, especially in the female offspring. However, the differences were small and thus, the biological significance of these changes is open to speculation. Overall, based on the results from two autoimmune models, we conclude that prenatal exposure to Cd did not lead to a measurable propensity to develop autoimmune disease later in life.
An autoregulation loop infust-1for circular RNA regulation inCaenorhabditis elegans
Authors: Cao Dong
Published: March 2021

Circular RNAs (circRNAs) are always expressed tissue-specifically, suggestive of specific factors that regulate their biogenesis. Here, taking advantage of available mutation strains of RNA binding proteins (RBPs) inCaenorhabditis elegans, I performed a screening of circRNA regulation in thirteen conserved RBPs. Among them, loss of FUST-1, the homolog of FUS (Fused in Sarcoma), caused downregulation of multiple circRNAs. By rescue experiments, I confirmed FUST-1 as a circRNA regulator. Further, I showed that FUST-1 regulates circRNA formation without affecting the levels of the cognate linear mRNAs. When recognizing circRNA pre-mRNAs, FUST-1 can affect both exon-skipping and circRNA in the same genes. Moreover, I identified an autoregulation loop infust-1, where FUST-1, isoform a promotes the skipping of exon 5 of its own pre-mRNA, which produces FUST-1, isoform b with different N-terminal sequences. FUST-1, isoform a is the functional isoform in circRNA regulation. Although FUST-1, isoform b has the same functional domains as isoform a, it cannot regulate either exon-skipping or circRNA formation.
Task-specific modulation of corticospinal neuron activity during skilled motor learning
Authors: Serradj Najet , Marino Francesca , Moreno-López Yunuen , Bernstein Amanda , Agger Sydney , Soliman Marwa , Sloan Andrew , Hollis Edmund
Published: March 2021

The learning of motor skills relies on plasticity of the primary motor cortex as task acquisition drives the remodeling of cortical motor networks1,2. Large scale cortical remodeling of evoked motor outputs occurs in response to the learning of skilled, corticospinal-dependent behavior, but not simple, unskilled tasks1. Here we determine the response of corticospinal neurons to both skilled and unskilled motor training and assess the role of corticospinal neuron activity in the execution of the trained behaviors. Usingin vivocalcium imaging, we found temporal coding of corticospinal activity coincided with the development of skilled, but not unskilled, motor expertise. Animals that failed to learn our skilled, precision isometric pull task exhibited a limited repertoire of dynamic movements and reduced network modulation. Transection of the corticospinal tract and optogenetic regulation of corticospinal activity show the necessity for patterned corticospinal network activity in the execution of skilled, but not unskilled, movement. We reveal a critical role for corticospinal network modulation in the learning and execution of skilled motor movements. The integrity of the corticospinal tract is essential to the recovery of dexterous movement after central nervous system injuries and these findings should help to shape translational approaches to motor recovery.
Functional diversity alters the effects of a pulse perturbation on the dynamics of tritrophic food webs
Authors: Ceulemans Ruben , Wojcik Laurie Anne , Gaedke Ursula
Published: March 2021

Biodiversity decline causes a loss of functional diversity, which threatens ecosystems through a dangerous feedback loop: this loss may hamper ecosystems’ ability to buffer environmental changes, leading to further biodiversity losses. In this context, the increasing frequency of climate and human-induced excessive loading of nutrients causes major problems in aquatic systems. Previous studies investigating how functional diversity influences the response of food webs to disturbances have mainly considered systems with at most two functionally diverse trophic levels. Here, we investigate the effects of a nutrient pulse on the resistance, resilience and elasticity of a tritrophic—and thus more realistic—plankton food web model depending on its functional diversity. We compare a non-adaptive food chain with no diversity to a highly diverse food web with three adaptive trophic levels. The species fitness differences are balanced through trade-offs between defense/growth rate for prey and selectivity/half-saturation constant for predators. We showed that the resistance, resilience and elasticity of tritrophic food webs decreased with larger perturbation sizes and depended on the state of the system when the perturbation occured. Importantly, we found that a more diverse food web was generally more resistant, resilient, and elastic. Particularly, functional diversity dampened the probability of a regime shift towards a non-desirable alternative state. In addition, despite the complex influence of the shape and type of the dynamical attractors, the basal-intermediate interaction determined the robustness against a nutrient pulse. This relationship was strongly influenced by the diversity present and the third trophic level. Overall, using a food web model of realistic complexity, this study confirms the destructive potential of the positive feedback loop between biodiversity loss and robustness, by uncovering mechanisms leading to a decrease in resistance, resilience and elasticity as functional diversity declines.
LPS core type diversity in the Escherichia coli species and associations with phylogeny and virulence gene repertoire
Authors: Leclercq Sébastien , Branger Maxime , Smith David GE , Germon Pierre
Published: March 2021

Escherichia coli is a very versatile species for which diversity has been explored from various perspectives highlighting, for example, phylogenetic groupings, pathovars as well as a wide range of O serotypes. The highly variable O-antigen, the most external part of the lipopolysaccharide component of the outer membrane of E. coli, is linked to the innermost lipid A through the core region of LPS of which 5 different structures, denominated K-12, R1, R2, R3 and R4, have been characterized so far. The aim of the present study was to analyze the prevalence of these LPS core types in the E. coli species and explore their distribution in the different E. coli phylogenetic groups and in relationship with the virulence gene repertoire. Results indicated an uneven distribution of core types between the different phylogroups, with phylogroup A strains being the most diverse in terms of LPS core types while phylogroups B1, D and E strains were dominated by the R3 type and phylogroups B2 and C strains being dominated by the R1 type. Strains carrying the LEE virulence operon were mostly of the R3 type whatever the phylogroup while, within phylogroup B2, strains carrying a K-12 core all belonged to the complex STc131, one of the major clone of extra-intestinal pathogenic E. coli (ExPEC) strains. The origin of this uneven distribution is discussed but remains to be explained, as well as the consequences of carrying a specific core type on the physiology of the bacteria.

IMPACT STATEMENT

The diversity of the E. coli species in terms of type of infections is well known, and its surface O-antigen which shows some correspondence to pathogenicity. This study is the first one to report in detail the diversity and distribution of the LPS core types in the E. coli species using whole genome sequences. This distribution of the 5 know core types is analyzed in the different phylogroups along with their association with specific virulence gene repertoire. Results indicate a non-random distribution of LPS core types in the E. coli species and, most interestingly, preferential association of certain core types with either some phylogenetic clades or with particular virulence gene repertoires. This work is a first step towards the identification of the origin of this diversity as well as towards the exploration of the physiological properties associated with specific core types.

DATA SUMMARY

Complete list of strains with associated data is available in supplementary table S1.
Population diversity of cassava mosaic begomoviruses increases over the course of serial vegetative propagation
Authors: Aimone Catherine D. , Lavington Erik , Hoyer J. Steen , Deppong David O. , Mickelson-Young Leigh , Jacobson Alana , Kennedy George G. , Carbone Ignazio , Hanley-Bowdoin Linda , Duffy Siobain
Published: March 2021

Cassava mosaic disease (CMD) represents a serious threat to cassava, a major root crop for more than 300 million Africans. CMD is caused by single-stranded DNA begomoviruses that evolve rapidly, making it challenging to develop durable disease resistance. In addition to the evolutionary forces of mutation, recombination, and reassortment, factors such as climate, agriculture practices, and the presence of DNA satellites may impact viral diversity. To gain insight into the factors that alter and shape viral diversityin planta, we used high-throughput sequencing to characterize the accumulation of nucleotide diversity after inoculation of infectious clones corresponding to African cassava mosaic virus (ACMV) and East African cassava mosaic Cameroon virus (EACMCV) in the susceptible cassava landrace Kibandameno. We found that vegetative propagation had a significant effect on viral nucleotide diversity, while temperature and a satellite DNA did not have measurable impacts in our study. EACMCV diversity increased linearly with the number of vegetative propagation passages, while ACMV diversity increased for a time and then decreased in later passages. We observed a substitution bias toward C→T and G→A for mutations in the viral genomes consistent with field isolates. Non-coding regions excluding the promoter regions of genes showed the highest levels of nucleotide diversity for each genome component. Changes in the 5’ intergenic region of DNA-A resembled the sequence of the cognate DNA-B sequence. The majority of nucleotide changes in coding regions were non-synonymous, most with predicted deleterious effects on protein structure, indicative of relaxed selection pressure over 6 vegetative passages. Overall, these results underscore the importance of knowing how cropping practices affect viral evolution and disease progression.
A chromosome-level genome assembly of the European Beech (Fagus sylvatica) reveals anomalies for organelle DNA integration, repeat content and distribution of SNPs
Authors: Mishra Bagdevi , Ulaszewski Bartosz , Meger Joanna , Aury Jean-Marc , Bodénès Catherine , Lesur-Kupin Isabelle , Pfenninger Markus , Silva Corinne Da , Gupta Deepak K , Guichoux Erwan , Heer Katrin , Lalanne Céline , Labadie Karine , Opgenoorth Lars , Ploch Sebastian , Provost Grégoire Le , Salse Jérôme , Scotti Ivan , Wötzel Stefan , Plomion Christophe , Burczyk Jaroslaw , Thines Marco
Published: March 2021

The European Beech is the dominant climax tree in most regions of Central Europe and valued for its ecological versatility and hardwood timber. Even though a draft genome has been published recently, higher resolution is required for studying aspects of genome architecture and recombination. Here we present a chromosome-level assembly of the more than 300 year-old reference individual, Bhaga, from the Kellerwald-Edersee National Park (Germany). Its nuclear genome of 541 Mb was resolved into 12 chromosomes varying in length between 28 Mb and 73 Mb. Multiple nuclear insertions of parts of the chloroplast genome were observed, with one region on chromosome 11 spanning more than 2 Mb of the genome in which fragments up to 54,784 bp long and covering the whole chloroplast genome were inserted randomly. Unlike inArabidopsis thaliana, ribosomal cistrons are present inFagus sylvaticaonly in four major regions, in line with FISH studies. On most assembled chromosomes, telomeric repeats were found at both ends, while centromeric repeats were found to be scattered throughout the genome apart from their main occurrence per chromosome. The genome- wide distribution of SNPs was evaluated using a second individual from Jamy Nature Reserve (Poland). SNPs, repeat elements and duplicated genes were unevenly distributed in the genomes, with one major anomaly on chromosome 4. The genome presented here adds to the available highly resolved plant genomes and we hope it will serve as a valuable basis for future research on genome architecture and for understanding the past and future of European Beech populations in a changing climate.
Revealing Notch-dependencies in synaptic targets associated with Alzheimer’s disease
Authors: Perna A. , Marathe S. , Dreos R. , Falquet L. , Akarsu H. , Auber L. Alberi
Published: March 2021

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the major cause of dementia. There is evidence that synaptic dysfunction and perturbation of Excitatory/Inhibitory (E/I) balance arise at the early stages of AD, altering the normal neural network activity, and leading to cognitive decline. Recent studies have identified Notch signaling as a contributor of neurodegenerative advancement including AD pathophysiology. As part of the efforts to understand molecular mechanisms and players involved in cognitive decline, we employed transgenic mouse models with Notch1 and RBPJK loss of function (LOF) in pyramidal neurons of the CA fields. Using bulk RNAseq. We have investigated the differential expression of Notch-dependent genes either upon environmental enrichment (EE) or upon Kainate injury (KA). We found a substantial genetic diversity in absence of both Notch1 receptor or Rbpjk transcriptional activator. Among differentially expressed genes, we observed a significant upregulation of Gabra2a in both knockout models, suggesting a role for Notch signaling in the modulation of E/I balance. Upon neuroexcitotoxic stimulation, loss of Rbpjk results in decreased expression of synaptic proteins with neuroprotective effects. We confirmed Nptx2, Npy, Pdch8, TncC as direct Notch1/Rbpjk targets and Bdnf and Scg2 as indirect targets. Finally, we translate these findings into human entorhinal cortex containing the hippocampal region from Alzheimer’s Disease patients performing targeted transcripts analysis. We observe an increased trend for Rbpjk and the ligand DNER but not Notch1 expression. On the other hand, neuron-specific targets, Nptx2, Npy, BDNF and Gabra2a are upregulated during the mild-moderate stage, and decline in the severe phase of the disease. These findings identify Notch as a promising signaling cascade to fine-tune in order to ameliorate synaptic transmission and memory deficits that occur during early phase of the Alzheimer’s Disease.

Highlights

Loss of canonical and/or non-canonical Notch1 signaling in pyramidal neurons of the hippocampal CA field mainly affects the post-synaptic compartment.

In both RBPJKcKO and Notch1cKO mouse models there is upregulation of GABAergic receptor subunit alpha2 (Gabra2a).

The plasticity genes: Npy, Nptx2,Pcdh8 and TncC with neuroprotective functions and known association with Alzheimer’s Disease are direct Notch/Rbpjk targets.

During the mild-moderate stage of AD dementia, Notch canonical signaling promotes the expression of neuroprotective proteins, in the attempt of mitigating the effect of the excitatory-inhibitory imbalance. This activity is not observed during severe stages of the disease.
Numerical study of the second harmonic generation in FELs
Authors: Kalitenko A. M.
Published: March 2021

A numerical study of the effect of betatron oscillations on the second harmonic generation in free-electron lasers (FELs) is presented. Analytical expressions for the effective coupling strength factors are derived that clearly distinguish all contributions in subharmonics and each polarization of the radiation. A three-dimensional time-dependent numerical FEL code that takes into account the main FEL effects and the individual contribution of each electron to the second harmonic generation is presented. Also, the X- and Y-polarizations of the second harmonic are analyzed. The second harmonic was detected in experiments at the Advanced Photon Source (APS) Low Energy Undulator Test Line (LEUTL) and Linac Coherent Light Source (LCLS) in the soft X-ray regime. The approach presented in the article can be useful for a comprehensive study and diagnostics of XFELs. In the paper, the LCLS and Pohang Accelerator Laboratory X-ray Free-Electron Laser (PAL-XFEL) experiments are modeled. The simulation results are in a good agreement with the experimental data.
Fluid-structure interaction computational analysis and experiments of tsunami bore forces on coastal bridges
Authors: Mazinani Iman , Sarafraz Mohammad Mohsen , Ismail Zubaidah , Hashim Ahmad Mustafa , Safaei Mohammad Reza , Wongwises Somchai
Published: March 2021

Purpose

Two disastrous Tsunamis, one on the west coast of Sumatra Island, Indonesia, in 2004 and another in North East Japan in 2011, had seriously destroyed a large number of bridges. Thus, experimental tests in a wave flume and a fluid structure interaction (FSI) analysis were constructed to gain insight into tsunami bore force on coastal bridges.

Design/methodology/approach

Various wave heights and shallow water were used in the experiments and computational process. A 1:40 scaled concrete bridge model was placed in mild beach profile similar to a 24 × 1.5 × 2 m wave flume for the experimental investigation. An Arbitrary Lagrange Euler formulation for the propagation of tsunami solitary and bore waves by an FSI package of LS-DYNA on high-performance computing system was used to evaluate the experimental results.

Findings

The excellent agreement between experiments and computational simulation is shown in results. The results showed that the fully coupled FSI models could capture the tsunami wave force accurately for all ranges of wave heights and shallow depths. The effects of the overturning moment, horizontal, uplift and impact forces on a pier and deck of the bridge were evaluated in this research.

Originality/value

Photos and videos captured during the Indian Ocean tsunami in 2004 and the 2011 Japan tsunami showed solitary tsunami waves breaking offshore, along with an extremely turbulent tsunami-induced bore propagating toward shore with significantly higher velocity. Consequently, the outcomes of this current experimental and numerical study are highly relevant to the evaluation of tsunami bore forces on the coastal, over sea or river bridges. These experiments assessed tsunami wave forces on deck pier showing the complete response of the coastal bridge over water.