bluuebunny/crossref_metadata_2025 huggingface dataset:
Linking rhizosphere processes across scales: Opinion
Authors: Schnepf A. , Carminati A. , Ahmed M. A. , Ani M. , Benard P. , Bentz J. , Bonkowski M. , Brax M. , Diehl D. , Duddek P. , Kröner E. , Javaux M. , Landl M. , Lehndorff E. , Lippold E. , Lieu A. , Mueller C. W. , Oburger E. , Otten W. , Portell X. , Phalempin M. , Prechtel A. , Schulz R. , Vanderborght J. , Vetterlein D.
Published: July 2021

Purpose

Simultaneously interacting small-scale rhizosphere processes determine emergent plant-scale behaviour, including growth, transpiration, nutrient uptake, soil carbon storage and transformation by microorganisms. Current advances in modelling and experimental methods open the path to unravel and link those processes.

Methods

We present a series of examples of state-of-the art simulations addressing this multi-scale, multi-process problem from a modelling point of view, as well as from the point of view of integrating newly available rhizosphere data and images.

Results

Each example includes a model that links scales and experimental data to set-up simulations that explain and predict spatial and temporal distribution of rhizodeposition as driven by root architecture development, soil structure, presence of root hairs, soil water content and distribution of soil water. Furthermore, two models explicitly simulate the impact of the rhizodeposits on plant nutrient uptake and soil microbial activity, respectively. This exemplifies the currently available state of the art modelling tools in this field: image-based modelling, pore-scale modelling, continuum scale modelling and functional-structural plant modelling. We further show how to link the pore scale to the continuum scale by homogenisation or by deriving effective physical parameters like viscosity from nano-scale chemical properties.

Conclusion

Modelling allows to integrate and make use of new experimental data across different rhizosphere processes (and thus across different disciplines) and scales. Described models are tools to test hypotheses and consequently improve our mechanistic understanding of how rhizosphere processes impact plant-scale behaviour. Linking multiple scales and processes is the logical next step for future research.
Implications of trade network structure and population dynamics for food security and equality
Authors: Fair Kathyrn R , Bauch Chris T , Anand Madhur
Published: July 2021

Given trade’s importance to maintaining food security, it is crucial to understand the relationship between human population growth, land use, food supply, and trade. We develop a metapopulation model coupling human population dynamics to agricultural land use and food production in “patches” (regions and countries) connected via trade networks. Patches that import sparingly or fail to adjust their demand sharply in response to changes in food per capita experience food insecurity. They fall into a feedback loop between increasing population growth and decreasing food per capita, particularly if they are peripheral to the network. A displacement effect is also evident; patches that are more central and/or import more heavily preserve their natural land states. Their reliance on imports means other patches must expand their agricultural land. These results emphasize that strategies for improving food security and equality must account for the combined effects of network topology and patch-level characteristics.
On the Etiology of Aesthetic Chills: a Behavioral Genetic Study
Authors: Bignardi Giacomo , Chamberlain Rebecca , Kevenaar Sofieke T , Tamimy Zenab , Boomsma Dorret I
Published: July 2021

Aesthetic chills, broadly defined as a somatic marker of peak emotional-hedonic responses, are experienced by individuals across a variety of human cultures. Yet individuals vary widely in the propensity of feeling them. These individual differences have been studied in relation to demographics, personality, and neurobiological and physiological factors, but no study to date has explored the genetic etiological sources of variation. To partition genetic and environmental sources of variation in the propensity of feeling aesthetic chills, we fitted a biometrical genetic model to data from 14127 twins (from 8995 pairs), collected by the Netherlands Twin Register. Both genetic and unique environmental factors accounted for variance in aesthetic chills, with heritability estimated at .36 ([.33, .39] 95% CI). We found females more prone than males to report feeling aesthetic chills. However, a test for genotype x sex interaction did not show evidence that heritability differs between sexes. We thus show that the propensity of feeling aesthetic chills is not shaped by nurture alone, but it also reflects underlying genetic propensities.
scSGL: Signed Graph Learning for Single-Cell Gene Regulatory Network Inference
Authors: Karaaslanli Abdullah , Saha Satabdi , Aviyente Selin , Maiti Tapabrata
Published: July 2021

Motivation

Elucidating the topology of gene regulatory networks (GRNs) from large single-cell RNA sequencing (scRNAseq) datasets, while effectively capturing its inherent cell-cycle heterogeneity and dropouts, is currently one of the most pressing problems in computational systems biology. Recently, graph learning (GL) approaches based on graph signal processing (GSP) have been developed to infer graph topology from signals defined on graphs. However, existing GL methods are not suitable for learning signed graphs, which represent a characteristic feature of GRNs, as they account for both activating and inhibitory relationships between genes. They are also incapable of handling high proportion of zero values, which represent dropouts in single cell experiments. To this end, we propose a novel signed GL approach, scSGL, that learns GRNs based on the assumption of the smoothness and non-smoothness of gene expressions over activating and inhibitory edges, respectively. scSGL is then extended with kernels to take the nonlinearity of co-expressions into account and handle high proportion of dropouts. From GSP perspective, this extension corresponds to assuming smoothness/non-smoothness of graph signals in a higher dimensional space defined by the kernel. The proposed approach is formulated as a non-convex optimization problem and solved using an efficient ADMM framework.

Results

In our experiments on simulated and real single cell datasets, scSGL compares favorably with other single cell gene regulatory network reconstruction algorithms.

Availability

The scSGL code and analysis scripts are available at (https://github.com/Single-Cell-Graph-Learning/scSGL).
Stochastic comparison of synchronization in activator- and repressor-based coupled gene oscillators
Authors: Shamim Ul Hasan A B M , Dey Supravat , Kurata Hiroyuki , Singh Abhyudai
Published: July 2021

Inside living cells, proteins or mRNA can show oscillations even without a periodic driving force. Such genetic oscillations are precise timekeepers for cell-cycle regulations, pattern formation during embryonic development in higher animals, and daily cycle maintenance in most organisms. The synchronization between oscillations in adjacent cells happens via intercellular coupling, which is essential for periodic segmentation formation in vertebrates and other biological processes. While molecular mechanisms of generating sustained oscillations are quite well understood, how do simple intercellular coupling produces robust synchronizations are still poorly understood? To address this question, we investigate two models of coupled gene oscillators - activator-based coupled oscillators (ACO) and repressor-based coupled oscillators (RCO) models. In our study, a single autonomous oscillator (that operates in a single cell) is based on a negative feedback, which is delayed by intracellular dynamics of an intermediate species. For the ACO model (RCO), the repressor protein of one cell activates (represses) the production of another protein in the neighbouring cell after a intercellular time delay. We investigate the coupled models in the presence of intrinsic noise due to the inherent stochasticity of the biochemical reactions. We analyze the collective oscillations from stochastic trajectories in the presence and absence of explicit coupling delay and make careful comparison between two models. Our results show no clear synchronizations in the ACO model when the coupling time delay is zero. However, a non-zero coupling delay can lead to anti-phase synchronizations in ACO. Interestingly, the RCO model shows robust in-phase synchronizations in the presence and absence of the coupling time delay. Our results suggest that the naturally occurring intercellular couplings might be based on repression rather than activation where in-phase synchronization is crucial.
Identifying patients at high risk of inappropriate drug dosing in periods with renal dysfunction
Authors: Kaas-Hansen Benjamin Skov , Rodríguez Cristina Leal , Placido Davide , Thorsen-Meyer Hans-Christian , Nielsen Anna Pors , Dérian Nicolas , Brunak Søren , Andersen Stig Ejdrup
Published: July 2021

Introduction

Dosing of renally cleared drugs in patients with kidney failure often deviates from clinical guidelines but little is known about what is predictive of receiving inappropriate doses.

Methods and materials

We combined data from the Danish National Patient Register and in-hospital data on drug administrations and estimated glomerular filtration rates for admissions between 1 October 2009 and 1 June 2016, from a pool of about 2.9 million persons. We trained artificial neural network and linear logistic ridge regression models to predict the risk of five outcomes (>0, ≥1, ≥2, ≥3 and ≥5 inappropriate doses daily) with index set 24 hours after admission. We used time-series validation for evaluating discrimination, calibration, clinical utility and explanations.

Results

Of 52,451 admissions included, 42,250 (81%) were used for model development. The median age was 77 years; 50% of admissions were of women. ≥5 drugs were used between admission start and index in 23,124 admissions (44%); the most common drug classes were analgesics, systemic antibacterials, diuretics, antithrombotics, and antacids. The neural network models had better discriminative power (all AUROCs between 0.77 and 0.81) and were better calibrated than their linear counterparts. The main prediction drivers were use of anti-inflammatory, antidiabetic and anti-Parkison’s drugs as well as having a diagnosis of chronic kidney failure. Sex and age affected predictions but slightly.

Conclusion

Our models can flag patients at high risk of receiving at least one inappropriate dose daily in a controlled in-silico setting. A prospective clinical study may confirm this holds in real-life settings and translates into benefits in hard endpoints.
Genetic regulation ofOAS1nonsense-mediated decay underlies association with risk of severe COVID-19
Authors: Banday A Rouf , Stanifer Megan L , Florez-Vargas Oscar , Onabajo Olusegun O , Zahoor Muhammad A , Papenberg Brenen W , Ring Timothy J , Lee Chia-Han , Andreakos Evangelos , Arons Evgeny , Barsh Greg , Biesecker Leslie G , Boyle David L , Burnett-Hartman Andrea , Carrington Mary , Chang Euijin , Choe Pyoeng Gyun , Chrisholm Rex L , Dalgard Clifton , Edberg Jeff , Erdmann Nathan , Feigelson Heather S , Firestein Gary S , Gehring Adam J , Ho Michelle , Holland Steven , Hutchinson Amy A , Im Hogune , Ison Michael G , Kim Hong Bin , Kreitman Robert J , Korf Bruce R , Mirabello Lisa , Pacheco Jennifer A , Peluso Michael J , Rader Daniel J , Redden David T , Ritchie Marylyn D , Rosenbloom Brooke , Sant Anna Hanaisa P , Savage Sharon , Siouti Eleni , Triantafyllia Vasiliki , Vargas Joselin M , Verma Anurag , Vij Vibha , Wesemann Duane R , Yeager Meredith , Yu Xu , Zhang Yu , Boulant Steeve , Chanock Stephen J , Feld Jordan J , Prokunina-Olsson Ludmila
Published: July 2021

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76OAS1variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay ofOAS1. We suggest that genetically-regulated loss ofOAS1expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of theOAS1risk haplotypes.
Using big data analytics to explore the relationship between government stringency and preventative social behaviour during the COVID-19 pandemic in the United Kingdom
Authors: Al-Zubaidy Noor , Crespo Roberto , Jones Sarah , Drikvandi Reza , Gould Lisa , Leis Melanie , Maheswaran Hendramoorty , Neves Ana Luisa , Darzi Ara
Published: July 2021

We evaluated the association between preventative social behaviour and government stringency. Additionally, we sought to evaluate the influence of additional factors including time, need to protect others (using the reported number of COVID-19 deaths as a surrogate measure) and reported confidence in government handling of the COVID-19 pandemic. We used repeated national cross-sectional surveys the UK over the course of 41 weeks from 1st April 2020 to January 28th, 2021, including a total of 38,092 participants. Preventative social behaviour and government stringency index scores were significantly associated on linear regression analyses (R2 =0.6468, p<0.001, and remained significant after controlling for the effect of reported COVID-19 deaths, confidence in government handling of the pandemic, and time (R2=0.898, p<0.001). Longitudinal data suggest that government stringency is an effective tool in promoting preventative social behaviour in the fight against COVID-19.
Single-cell transcriptomics for the 99.9% of species without reference genomes
Authors: Botvinnik Olga Borisovna , Vemuri Venkata Naga Pranathi , Pierce N. Tessa , Logan Phoenix Aja , Nafees Saba , Karanam Lekha , Travaglini Kyle Joseph , Ezran Camille Sophie , Ren Lili , Juang Yanyi , Wang Jianwei , Wang Jianbin , Brown C. Titus
Published: July 2021

Single-cell RNA-seq (scRNA-seq) is a powerful tool for cell type identification but is not readily applicable to organisms without well-annotated reference genomes. Of the approximately 10 million animal species predicted to exist on Earth, >99.9% do not have any submitted genome assembly. To enable scRNA-seq for the vast majority of animals on the planet, here we introduce the concept of “k-mer homology,” combining biochemical synonyms in degenerate protein alphabets with uniform data subsampling via MinHash into a pipeline called Kmermaid. Implementing this pipeline enables direct detection of similar cell types across species from transcriptomic data without the need for a reference genome. Underpinning Kmermaid is the tool Orpheum, a memory-efficient method for extracting high-confidence protein-coding sequences from RNA-seq data. After validating Kmermaid using datasets from human and mouse lung, we applied Kmermaid to the Chinese horseshoe bat (Rhinolophus sinicus), where we propagated cellular compartment labels at high fidelity. Our pipeline provides a high-throughput tool that enables analyses of transcriptomic data across divergent species’ transcriptomes in a genome- and gene annotation-agnostic manner. Thus, the combination of Kmermaid and Orpheum identifies cell type-specific sequences that may be missing from genome annotations and empowers molecular cellular phenotyping for novel model organisms and species.
A tail of plumage colouration: disentangling geographic, seasonal, and dietary effects on plumage colour in a migratory songbird
Authors: Mahoney Sean M. , Reudink Matthew W. , Contina Andrea , Roberts Kelly A. , Schabert Veronica T. , Gunther Emily G. , Covino Kristen M.
Published: July 2021

Plumage ornamentation in birds serves critical inter- and intra-sexual signaling functions. While carotenoid-based plumage colouration is often viewed as a classic condition-dependent sexually selected trait, plumage colouration can be influenced by a wide array of both intrinsic and extrinsic factors. Understanding the mechanisms underlying variation in colouration is especially important for species where the signaling function of ornamental traits is complex or the literature conflicting. Here, we examined variation in the yellow/orange tail feathers of American redstarts (Setophaga ruticilla) passing through two migratory stopover sites in eastern North America during both spring and fall migration to assess the role of geographic variation and seasonality in influencing feather colouration. In addition, we investigated whether diet during moult (inferred via stable isotope analysis of feather δ15N and δ13C) influenced plumage colouration. Our findings indicate that geographic variation, season, and diet all influence individual differences in American redstart colouration, represented by both traditional and tetrahedral colour variables. The extent to which these factors influence colour expression however is largely dependent on the colour metric under study, likely because different colour metrics reflect different attributes of the feather (e.g., structural components vs. pigment deposition). The effects of diet (δ15N) and season were pronounced for brightness, suggesting a strong effect of diet and feather wear/degradation on feather structure. Though hue, a metric that should strongly reflect pigment deposition, also changed from spring to fall, that effect was dependent on age, with only adults experiencing a reduction in ornamentation. Taken together, our results highlight the numerous sources of variation behind plumage coloration and underscores the difficulty of unraveling complex visual signaling systems, such as those in American redstarts.
α-Synuclein polymorphism determines oligodendroglial dysfunction
Authors: Frieg Benedikt , Geraets James A. , Strohäker Timo , Dienemann Christian , Mavroeidi Panagiota , Jung Byung Chul , Kim Woojin S. , Lee Seung-Jae , Xilouri Maria , Zweckstetter Markus , Schröder Gunnar F.
Published: July 2021

Synucleinopathies, such as Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are progressive and unremitting neurological diseases. For both PD and MSA, α-synuclein fibril inclusions inside brain cells are neuropathological hallmarks. In addition, amplification of α-synuclein fibrils from body fluids is a potential biomarker distinguishing PD from MSA. However, little is known about the structure of α-synuclein fibrils amplified from human samples and its connection to α-synuclein fibril structure in the human brain. Here we amplified α-synuclein fibrils from PD and MSA brain tissue, characterized its seeding potential in oligodendroglia, and determined the 3D structures by cryo-electron microscopy. We show that the α-synuclein fibrils from a MSA patient are more potent in recruiting the endogenous α-synuclein and evoking a redistribution of TPPP/p25α protein in mouse primary oligoden-droglial cultures compared to those amplified from a PD patient. Cryo-electron microscopy shows that the PD- and MSA-amplified α-synuclein fibrils share a similar protofilament fold but differ in their inter-protofilament interface. The structures of the brain-tissue amplified α-synuclein fibrils are also similar to other in vitro and ex vivo α-synuclein fibrils. Together with published data, our results suggest that αSyn fibrils differ between PD and MSA in their quaternary arrangement and could further vary between different forms of PD and MSA.
Successful microbial colonization of space using an anti-aggregation strategy
Authors: Liu Xiaonan , Wang Miaoxiao , Nie Yong , Wu Xiao-Lei
Published: July 2021

Many organisms live in habitats with limited nutrients or space, competition for these resources is ubiquitous. Although spatial factors related to population’s manner of colonizing space influences its success in spatial competition, what these factors are and to what extent they influence the outcome remains under-explored. Here, we applied a simulated competitive model to explore the spatial factors affecting outcomes of competition for space. By quantifying spatial factors using ‘Space Accessibility’, we show that colonizing space in an anti-aggregation manner contributes to microbial competitive success. We also find that the competitive edge derived from being anti-aggregation in colonizing space, which results in a higher ‘Space Accessibility’, neutralizes the disadvantage arising from either lower growth rate or lower initial abundance. These findings shed light on the role of space colonization manners on maintaining biodiversity within ecosystems and provide novel insights critical for understanding how competition for space drives evolutionary innovation.
Docking Molecular analysis of potential Drug Paritaprevir against Mycobacterium tuberculosis (Mtb)
Authors: Ferrari Ivan Vito , Patrizio Paolo
Published: July 2021

Background

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, which kills 1.8 million annually. This is an infectious disease generally affects the lungs, but can also affect other parts of the body. Mtb RNA polymerase (RNAP) is the target of the first-line antituberculosis drug Rifampin (Rif). We report first time a Potential Drug Paritaprevir against with severe infectious disease, by in Silico approach, using Autodock Vina and Autodock 4 (or MGL Tool), estimated with Pyrx and AMDock Software, calculating three different important parameters: Binding Affinity (kcal/mol), estimated Ki (in nM units) and Ligand Efficiency (L.E. in kcal/mol). After a selective analysis of over 1000 drugs, processed with Pyrx (a Virtual Screening software for Computational Drug Discovery) in the Ligand Binding site pocket of the protein (ID PDB 5UHB chain C,DNA-directed RNA polymerase subunit beta), we noticed high values of these 3 parameters mentioned above of Paritaprevir, concluding that it could be an excellent candidate drug for this type of infection. Indeed, from the results of Autodock Vina and Autodock 4 (or Autodock 4.2), implemented with lamarckian genetic algorithm, LGA, trough AMDock Software, This oral drug, approved by FDA in 2014, both by Autodock Vina and Autodock Vina 4 has excellent Binding affinity value, ca. −10.00 kcal/mol, a Ki value 40 nM and Ligand efficiency ca −0.15 kcal/mol. These results are comparable to the drug crystallized in the above-mentioned protein, currently used against TBC.
Biomechanical effects of the addition of a precision constraint on a collective load carriage task
Authors: Sghaier Nour , Fumery Guillaume , Fourcassié Vincent , Turpin Nicolas A. , Moretto Pierre
Published: July 2021

1

Team lifting is a complex and collective motor task that possesses both motor and cognitive components. The purpose of this study was to investigate to what extent the biomechanics of a collective load carriage is affected when a dyad of individuals is performing a carrying task with an additional accuracy constraint. Ten dyads performed a first condition in which they collectively transported a load (CC), and a second one in which they transported the same load while maintaining a ball in a target position on its top (PC).

The recovery-rate, amplitude, and period of the center-of-mass (COM) trajectory were computed for the whole system (dyad + table = PACS). We analyzed the forces and moments exerted at each joint of the upper limbs of the subjects. We observed a decrease in the overall performance of the dyads when the Precision task was added, i.e., i) the velocity and amplitude of CoMPACS decreased by 1,7% and 5,8%, respectively, ii) inter-subject variability of the Moment-Cost-Function decreased by 95% and recovery rate decreased by 19,2% during PC. A kinetic synergy analysis showed that the subjects reorganized their coordination in the PC.

Our results demonstrate that adding a precision task affects the economy of collective load carriage. Notwithstanding, the joint moments at the upper-limbs are better balanced and co-vary more across the paired subjects during the precision task. Our study results may find applications in domains such as Ergonomics, Robotics-developments, and Rehabilitation.
NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses
Authors: Wang Hongyun , Zhang Lu , Zeng Cong , Feng Jiangpeng , Wang Dehe , He Miao , Jiang Ao , Cao Yuanyuan , Guo Xiao , Liu Jiejie , Yan Kun , Tang Hao , Xu Ke , Fan Chengpeng , Guo Deyin , Lan Ke , Zhou Yu , Chen Yu
Published: July 2021

5-Methylcytosine (m5C) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes through regulating RNA metabolism. However, its regulatory role in antiviral innate immunity has not yet been elucidated. Here, we report that NSUN2, a typical m5C methyltransferase, can negatively regulate type I interferon responses during viral infection. NSUN2 specifically mediates m5C methylation ofIRF3mRNA and accelerates its degradation, resulting in low levels of IRF3 and downstream IFN-β production. Knockout or knockdown of NSUN2 could enhance type I interferon responses and downstream ISG expression after viral infectionin vitro. Andin vivo, the antiviral innate responses is more dramatically enhanced inNsun2+/−mice than inNsun2+/+mice. Four highly m5C methylated cytosines inIRF3mRNA were identified, and their mutation could enhance the cellularIRF3mRNA levels. Moreover, infection with Sendai virus (SeV), vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), Zika virus (ZIKV), or especially SARS-CoV-2 resulted in a reduction in endogenous levels of NSUN2. Together, our findings reveal that NSUN2 serves as a negative regulator of interferon response by accelerating the fast turnover ofIRF3mRNA, while endogenous NSUN2 levels decrease after viral infection to boost antiviral responses for the effective elimination of viruses. Our results suggest a paradigm of innate antiviral immune responses ingeniously involving NSUN2-mediated m5C modification.
The PD-1 checkpoint receptor maintains tolerance of self-reactive CD8 T cell in skin
Authors: Damo Martina , Cui Can , William Ivana , Hornick Noah I. , Kwok Darwin , Clulo Kathryn , Damsky William E. , Leventhal Jonathan S. , Joshi Nikhil S.
Published: July 2021

Peripheral tolerance is thought to result from anergy or deletion of self-reactive T cells shortly after antigen encounter. However, the frequent occurrences of immune-related Adverse Events (irAEs) following checkpoint inhibitor (CPI) treatment suggest a hypothesis that immunologically healthy individuals have self-reactive effector T cells that are kept in a non-pathogenic state through checkpoint receptor-mediated suppression, instead of anergy or deletion. We expressed self-antigens in healthy skin and found that antigen-specific CD8 T cells infiltrated the tissue, but remained tolerant, despite having a transcriptional program that resembled effector T cells found after CPIs. These self-reactive PD-1+ CD8 T cells drove IFNγ-dependent increases in PD-L1 on skin myeloid cells. Blockade of PD-1 or PD-1/CTLA-4 led to post-transcriptional upregulation of effector proteins by antigen-specific CD8 T cells and elimination of antigen-expressing epithelial cells, resulting in localized tissue pathology with features of human cutaneous irAEs. This data supports the hypothesis that myeloid cells in healthy skin prevent pathology from self-reactive effector CD8 T cells through the PD-1/PD-L1 pathway.
Nucleolar stress controls mutant Huntingtin toxicity and monitors Huntington’s disease progression
Authors: Sönmez Aynur , Mustafa Rasem , Ryll Salome T. , Tuorto Francesca , Wacheul Ludivine , Ponti Donatella , Litke Christian , Hering Tanja , Kojer Kerstin , Koch Jenniver , Pitzer Claudia , Kirsch Joachim , Neueder Andreas , Kreiner Grzegorz , Lafontaine Denis L.J. , Orth Michael , Liss Birgit , Parlato Rosanna
Published: July 2021

Transcriptional and cellular stress surveillance deficits are hallmarks of Huntington’s disease (HD), a fatal autosomal dominant neurodegenerative disorder, caused by a pathological expansion of CAG repeats in the Huntingtin (HTT)gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD remain unclear, the impact of nucleolar dysfunction on HD pathophysiologyin vivois elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases mHTT disperse state in the nucleus, exacerbating the motor deficits. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its nucleolar localization. NPM1 de-localization occurs in the striatum and in the skeletal muscle of the progressive zQ175 knock-in HD mouse model, mimicking the phenotype of HD patients in skeletal muscle biopsies. Taken together, we showed that nucleolar integrity regulates the formation of mHTT inclusionsin vivo, and identified NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.
Effects of blue monochromatic light directed at one eye of pregnant horse mares on gestation, parturition and foal maturity
Authors: Lutzer Anne , Nagel Christina , Murphy Barbara A. , Aurich Jörg , Wulf Manuela , Gautier Camille , Aurich Christine
Published: July 2021

Blue light directed at one eye advances the equine ovulatory season but can also advance foaling. In this study, effects of blue LED light on pregnancy outcome were assessed. Twenty mares with singleton pregnancies were studied over two consecutive years in a cross-over design. In one year, mares received an extended photoperiod using 50 lux of blue LED light (468 nm) directed at a single eye from 08:00 until 23:00 daily via head-worn light masks starting mid-December and in the other year remained untreated as controls. Gestation was shorter in blue LED light-treated (333.2±1.0 days,±SEM) than in control pregnancies (337.9±1.8 days, p<0.05). Colostral IgG content was lower in treated than in control pregnancies (p<0.05) but was adequate to ensure sufficient IgG transfer to newborn foals with a single exception. Foals born to blue LED light-treated mares had lower wither heights (102.5±1.1 vs. 105.2±1.0 cm, p<0.01), similar weights (55.0±1.3 vs. 55.5±1.1 kg) and took less time to stand after birth than control foals (39±3 vs. 56±4 min, p<0.05). The neutrophil/lymphocyte ratio, was higher in foals born to blue LED light-treated mares than controls (3.2±0.2 vs. 2.7±0.2; p<0.05). Foals born to blue LED light-treated mares had reduced hair length compared to controls (13.1±0.8 vs. 20.9±0.1 mm; p<0.001) and hair regrowth in treated mares was reduced (p<0.05). Maternal plasma prolactin concentration was increased in treated mares (p=0.05) and peaked at foaling (p<0.001). In conclusion, blue LED light directed at one eye advanced foaling and influenced height, hair coat and maturity in foals.
TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer’s disease hippocampus
Authors: Jayaraman Anusha , Htike Thein Than , James Rachel , Picon Carmen , Reynolds Richard
Published: July 2021

The pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimer’s disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many systemic chronic inflammatory and degenerative conditions and are amongst the key mediators of neuroinflammation. TNF binds to the TNFR1 and TNFR2 receptors to activate diverse cellular responses that can be either neuroprotective or neurodegenerative. In particular, TNF can induce programmed necrosis or necroptosis in an inflammatory environment. Although activation of necroptosis has recently been demonstrated in the AD brain, its significance in AD neuron loss and the role of TNF signaling is unclear. We demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 and MLKL, predominantly observed in the CA1 pyramidal neurons. The density of phosphoRIPK3+ and phosphoMLKL+ neurons correlated inversely with total neuron density and showed significant sexual dimorphism within the AD cohort. In addition, apoptotic signaling was not significantly activated in the AD brain compared to the control brain. Exposure of human iPSC-derived glutamatergic neurons to TNF increased necroptotic cell death when apoptosis was inhibited, which was significantly reversed by small molecule inhibitors of RIPK1, RIPK3, and MLKL. In the post-mortem AD brain and in human iPSC neurons to TNF, we show evidence of altered expression of proteins of the ESCRT III complex, which has been recently suggested as an antagonist of necroptosis and a possible mechanism by which cells can survive after necroptosis has been triggered. Taken together, our results suggest that neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis, which is amenable to therapeutic intervention at several points in the signaling pathway.
Study of Basic Local Alignment Search Tool (BLAST) and Multiple Sequence Alignment (Clustal- X) of Monoclonal mice/human antibodies
Authors: FERRARI IVAN VITO , PATRIZIO Paolo
Published: July 2021

In this work, we have focused on the study of the Basic Local Alignment Search Tool (BLAST) and Multiple Sequence Alignment (Clustal- X) of different monoclonal mice antibodies to understand better the multiple alignments of sequences. Our strategy was to compare the light chains of multiple monoclonal antibodies to each other, calculating their identity percentage and in which amino acid portion. (See below figure 2) Subsequently, the same survey of heavy chains was carried out with the same methodology. (See below figure 3) Finally, sequence alignment between the light chain of one antibody and the heavy chain of another antibody was studied to understand what happens if chains are exchanged between antibodies. (See below figure 4) From our results of BLAST estimation alignment, we have reported that the Light Chains (Ls) of Monoclonal Antibodies in Comparison have a sequence Homology of about 60-80% and they have a part identical in sequence zone in range 100-210 residues amino acids, except ID PDB 4ISV, which it turns out to have a 40% lower homology than the others antibodies. As far as, the heavy chains (Hs) of Monoclonal Antibodies are concerned, however they tend to have a less homology of sequences, compared to lights chains consideration, equal to 60%-70% and they have an identical part in the sequence zone between 150-210 residues amino acids; with the exception of ID PDB 3I9G-3W9D antibodies that have an equal homology at 50%. ( See supporting part) Summing up: about 70-80% identity among 2 light chains of 2 antibodies, 60-70% identity between 2 heavy chains of 2 antibodies, 30% identity between the two chains of a antibody and 30% if you compare the light chain of one antibody with the heavy chain of another antibody.
Sphingolipids are involved in Pieris brassicae egg-induced cell death in Arabidopsis thaliana
Authors: Groux Raphaël , Fouillen Laetitia , Mongrand Sébastien , Reymond Philippe
Published: July 2021

In Brassicaceae, hypersensitive-like (HR-like) cell death is a central component of direct defenses triggered against eggs of the large white butterfly Pieris brassicae. The signaling pathway leading to HR-like in Arabidopsis is mainly dependent on salicylic acid (SA) accumulation, but downstream components are unclear. Here, we found that treatment with P. brassicae egg extract (EE) trigger changes in expression of sphingolipid metabolism genes in Arabidopsis and Brassica nigra. Disruption of ceramide synthase activity led to a significant decrease of EE-induced HR-like whereas SA signaling and reactive oxygen species levels were unchanged, suggesting that ceramides are downstream activators of HR-like. Sphingolipid quantifications showed that ceramides with C16:0 side-chains accumulated in both species, and this response was independent on SA accumulation. Finally, we provide genetic evidence that the modification of fatty acyl chains of sphingolipids modulates HR-like. Altogether, these results show that sphingolipids play a key and specific role during insect egg-triggered HR-like.
An orthologous gene coevolution network provides insight into eukaryotic cellular and genomic structure and function
Authors: Steenwyk Jacob L. , Phillips Megan A. , Yang Feng , Date Swapneeta S. , Graham Todd R. , Berman Judith , Hittinger Chris Todd , Rokas Antonis
Published: July 2021

Orthologous gene coevolution—which refers to gene pairs whose evolutionary rates covary across speciation events—is often observed among functionally related genes. We present a comprehensive gene coevolution network inferred from the examination of nearly three million orthologous gene pairs from 332 budding yeast species spanning ∼400 million years of eukaryotic evolution. Modules within the network provide insight into cellular and genomic structure and function, such as genes functioning in distinct cellular compartments and DNA replication. Examination of the phenotypic impact of network perturbation across 14 environmental conditions using deletion mutant data from the baker’s yeast Saccharomyces cerevisiae suggests that fitness in diverse environments is impacted by orthologous gene neighborhood and connectivity. By mapping the network onto the chromosomes of S. cerevisiae and the opportunistic human pathogen Candida albicans, which diverged ∼235 million years ago, we discovered that coevolving orthologous genes are not clustered in either species; rather, they are most often located on different chromosomes or far apart on the same chromosome. The budding yeast coevolution network captures the hierarchy of eukaryotic cellular structure and function, provides a roadmap for genotype-to-phenotype discovery, and portrays the genome as an extensively linked ensemble of genes.
Contribution of Uremia to Ureaplasma-Induced Hyperammonemia
Authors: Fleming Derek , Patel Robin
Published: July 2021

Lung transplant recipients (LTRs) are vulnerable to unexplained hyperammonemia syndrome (HS) in the early post-operative period, a condition typically unresponsive to non-antibiotic interventions. Recently, we showed that HS in LTRs is strongly correlated with Ureaplasma infection of the respiratory tract. It is not well-understood what makes LTRs preferentially susceptible to this phenomenon, compared to other immunocompromised hosts. Ureaplasma species harbor highly active ureases that convert urea to ammonia and CO2, utilizing the generated transmembrane potential to synthesize ATP. Post-operative LTRs commonly experience renal failure, resulting in uremia. We hypothesized that uremia could be a potentiating comorbidity to the development of HS secondary to Ureaplasma infection in LTRs by providing increased substrate for ureaplasmal ureases. We designed a novel dialyzed flow system to test the ammonia producing capacity of four isolates of Ureaplasma parvum and six isolates of Ureaplasma urealyticum in media formulations relating to normal and uremic host conditions. For all isolates, growth under uremic conditions resulted in significantly increased ammonia production over 24 hours, despite similar end-point bacterial quantities. Specifically, the isolates produced, on average, 1776.52 [standard deviation=263.98] μmol/L more ammonia when grown under uremic compared to normal conditions. This suggests that uremia, common in early post-operative LTRs, is a plausible contributing factor to the phenomenon of Ureaplasma-induced HS in this patient population.
Minimal synthetic enhancers reveal control of the probability of transcriptional engagement and its timing by a morphogen gradient
Authors: Reimer Armando , Alamos Simon , Westrum Clay , Turner Meghan A. , Talledo Paul , Zhao Jiaxi , Garcia Hernan G
Published: July 2021

How enhancers interpret morphogen gradients to generate spatial patterns of gene expression is a central question in developmental biology. Although recent studies have begun to elucidate that enhancers can dictate whether, when, and at what rate a promoter will engage in transcription, the complexity of endogenous enhancers calls for theoretical models with too many free parameters to quantitatively dissect these regulatory strategies. To overcome this limitation, we established a minimal synthetic enhancer system in embryos of the fruit 2y Drosophila melanogaster. Here, a gradient of the Dorsal activator is read by a single Dorsal binding site. By quantifying transcriptional activity using live imaging, our experiments revealed that this single Dorsal binding site is capable of regulating whether promoters engage in transcription in a Dorsal concentration-speci1c manner. By modulating binding-site aZnity, we determined that a gene’s decision to engage in transcription and its transcriptional onset time can be explained by a simple theoretical model where the promoter has to traverse multiple kinetic barriers before transcription can ensue. The experimental platform developed here pushes the boundaries of live-imaging in studying gene regulation in the early embryo by enabling the quanti1cation of the transcriptional activity driven by a single transcription factor binding site, and making it possible to build more complex enhancers from the ground up in the context of a dialogue between theory and experiment.
Borgs are giant extrachromosomal elements with the potential to augment methane oxidation
Authors: Al-Shayeb Basem , Schoelmerich Marie C. , West-Roberts Jacob , Valentin-Alvarado Luis E. , Sachdeva Rohan , Mullen Susan , Crits-Christoph Alexander , Wilkins Michael J. , Williams Kenneth H. , Doudna Jennifer A. , Banfield Jillian F.
Published: July 2021

Anaerobic methane oxidation exerts a key control on greenhouse gas emissions1, yet factors that modulate the activity of microorganisms performing this function remain little explored. In studying groundwater, sediments, and wetland soil where methane production and oxidation occur, we discovered extraordinarily large, diverse DNA sequences that primarily encode hypothetical proteins. Four curated, complete genomes are linear, up to ~1 Mbp in length and share genome organization, including replicore structure, long inverted terminal repeats, and genome-wide unique perfect tandem direct repeats that are intergenic or generate amino acid repeats. We infer that these are a new type of archaeal extrachromosomal element with a distinct evolutionary origin. Gene sequence similarity, phylogeny, and local divergence of sequence composition indicate that many of their genes were assimilated from methane-oxidizingMethanoperedensarchaea. We refer to these elements as “Borgs”. We identified at least 19 different Borg types coexisting withMethanoperedensin four distinct ecosystems. Borg genes expand redox and respiratory capacity (e.g., clusters of multiheme cytochromes), ability to respond to changing environmental conditions, and likely augmentMethanoperedenscapacity for methane oxidation (e.g., methyl coenzyme M reductase). By this process, Borgs could play a previously unrecognized role in controlling greenhouse gas emissions.
De novo spatiotemporal modelling of cell-type signatures identifies novel cell populations in the developmental human heart
Authors: Salas Sergio Marco , Yuan Xiao , Sylven Christer , Nilsson Mats , Wählby Carolina , Partel Gabriele
Published: July 2021

With the emergence of high throughput single cell techniques, the understanding of cellular diversity in biologically complex processes has rapidly increased. The next step towards comprehension of e.g. key organs in the mammal development is to obtain spatiotemporal atlases of the cellular diversity. However, targeted cell typing approaches relying on existing single cell data achieve incomplete and biased maps that could mask the molecular and cellular heterogeneity present in a tissue slide. Here we applied spage2vec, a de novo approach to spatially resolve and characterize cellular diversity during human heart development. We obtained well defined spatial maps of tissue samples from 4.5 to 9 post conception weeks, not biased by probabilistic cell typing approaches. We found previously unreported molecular diversity within cardiomyocytes and epicardial cells and identified their characteristic expression signatures by matching them with specific subpopulations found in single cell RNA sequencing datasets.
Splicing Factor SRSF1 Deficiency in the Liver Triggers NASH-like Pathology via R-Loop Induced DNA Damage and Cell Death
Authors: Arif Waqar , Mathur Bhoomika , Saikali Michael F. , Chembazhi Ullas V. , Blue Steven M. , Yee Brian A. , Van Nostrand Eric L. , Bangru Sushant , Hao Qinyu , Yeo Gene W. , Prasanth Kannanganattu V. , Anakk Sayeepriyadarshini , Cummins Carolyn L. , Kalsotra Auinash
Published: July 2021

Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is primarily mediated by the excessive formation of deleterious RNA–DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Lipid accumulation in SRSF1-deficient hepatocytes is followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. Importantly, SRSF1-depleted human liver cancer cells recapitulate this pathogenesis illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how accumulation of detrimental R-loops impedes hepatocellular gene expression, triggering metabolic derangements and liver failure.
A mouse-adapted SARS-CoV-2 strain replicating in standard laboratory mice
Authors: Montagutelli Xavier , Prot Matthieu , Jouvion Grégory , Levillayer Laurine , Conquet Laurine , Reyes-Gomez Edouard , Donati Flora , Albert Melanie , van der Werf Sylvie , Jaubert Jean , Simon-Lorière Etienne
Published: July 2021

SARS-CoV-2 has infected almost 200 million humans and caused over 4 million deaths worldwide. Evaluating countermeasures and improving our understanding of COVID-19 pathophysiology require access to animal models that replicate the hallmarks of human disease. Mouse infection with SARS-CoV-2 is limited by poor affinity between the virus spike protein and its cellular receptor ACE2. We have developed by serial passages the MACo3 virus strain which efficiently replicates in the lungs of standard mouse strains and induces age-dependent lung lesions. Compared to other mouse-adapted strains and severe mouse models, infection with MACo3 results in mild to moderate disease and will be useful to investigate the role of host genetics and other factors modulating COVID-19 severity.