bluuebunny/crossref_metadata_2025 huggingface dataset:
Plxdc family members are novel receptors for the rhesus monkey rhadinovirus (RRV)
Authors: Großkopf Anna K. , Schlagowski Sarah , Fricke Thomas , Ensser Armin , Desrosiers Ronald C. , Hahn Alexander S.
Published: January 2020

The rhesus monkey rhadinovirus (RRV), a γ2-herpesvirus of rhesus macaques, shares many biological features with the human pathogenic Kaposi’s sarcoma-associated herpesvirus (KSHV). Both viruses, as well as the more distantly related Epstein-Barr virus, engage cellular receptors from the Eph family of receptor tyrosine kinases (Ephs). However, the importance of the Eph interaction for RRV entry varies between cell types suggesting the existence of Eph-independent entry pathways. We therefore aimed to identify additional cellular receptors for RRV by affinity enrichment and mass spectrometry. We identified an additional receptor family, the Plexin domain containing proteins 1 and 2 (Plxdc1/2) that bind the RRV gH/gL glycoprotein complex. Preincubation of RRV with soluble Plxdc2 decoy receptor reduced infection by approx. 60%, while overexpression of Plxdc1 and 2 dramatically enhanced RRV susceptibility of otherwise marginally permissive Raji cells. While the Plxdc2 interaction is conserved between two RRV strains, 26-95 and 17577, Plxdc1 specifically interacts with RRV 26-95 gH. The Plxdc interaction is mediated by a short motif at the N-terminus of RRV gH that is partially conserved between isolate 26-95 and isolate 17577, but absent in KSHV gH. Mutation of this motif abrogated the interaction with Plxdc1/2 inin vitroassays and reduced RRV infection in a cell-type specific manner. Taken together, our findings characterize Plxdc1/2 as novel interaction partners and entry receptors for RRV and support the concept of the N-terminal domain of the gammaherpesviral gH/gL complex as a multifunctional receptor-binding domain. Further, Plxdc1/2 usage defines an important biological difference between KSHV and RRV.

AUTHORS SUMMARY

KSHV is the causative agent of a group of malignancies which account for a substantial disease burden in particular in sub-Saharan Africa. RRV, a related virus of rhesus macaques, has shown promise as model system for KSHV and for the development of immunization strategies. To exploit the full potential of the RRV animal model system, detailed knowledge of commonalities and differences between KSHV and RRV is key. Here, we describe the Plexin domain containing proteins 1 and 2 as a novel receptor family which mediates entry of RRV, but not of KSHV. Infection experiments using RRV mutants deleted of the Plxdc interaction motif suggest a cell type-specific contribution of Plxdc receptors to RRV infection. As information on Plxdc1/2 and its biological function is still sparse, analysis of the RRV–Plxdc interaction will help to characterize the physiological and pathophysiological role of this receptor family.
PHENSIM: Phenotype Simulator
Authors: Alaimo Salvatore , Rapicavoli Rosaria Valentina , Marceca Gioacchino P. , La Ferlita Alessandro , Serebrennikova Oksana B. , Tsichlis Philip N. , Mishra Bud , Pulvirenti Alfredo , Ferro Alfredo
Published: January 2020

Despite the unprecedented growth in our understanding of cell biology, it still remains challenging to connect it to experimental data obtained with cells and tissues’ physiopathological status under precise circumstances. This knowledge gap often results in difficulties in designing validation experiments, which are usually labor-intensive, expensive to perform, and hard to interpret.

Here we propose PHENSIM, a computational tool using a systems biology approach in order to simulate how cell phenotypes are affected by the activation/inhibition of one or multiple biomolecules and does so by exploiting signaling pathways. Our tool’s applications include predicting the outcome of drug administration, knockdown experiments, gene transduction, and exposure to exosomal cargo. Importantly, PHENSIM enables the user to make inferences on well-defined cell lines and includes pathway maps from three different model organisms. To assess our approach’s reliability, we built a benchmark from transcriptomics data gathered from NCBI GEO and performed four case studies on known biological experiments. Our results show high prediction accuracy, thus highlighting the capabilities of this methodology.

PHENSIM standalone Java application is available athttps://github.com/alaimos/phensim, along with all data and source codes for benchmarking. A web-based user interface is accessible athttps://phensim.atlas.dmi.unict.it/.
Suitable habitats of fish species in the Barents Sea
Authors: Husson Bérengère , Certain Gregoire , Filin Anatoly , Planque Benjamin
Published: January 2020

Many marine species are shifting their distribution poleward in response to climate change. The Barents Sea, as a doorstep to the fast-warming Arctic, is experiencing large scale changes in its environment and its communities. This paper aims at understanding what environmental predictors limit fish species habitats in the Barents Sea and discuss their possible evolution in response to the warming of the Arctic.

Species distribution models usually aim at predicting the probability of presence or the average abundance of a species, conditional on environmental drivers. A complementary approach is to determine suitable habitats by modelling the upper limit of a species’ response to environmental factors. Using quantile regressions, we model the upper limit of biomass for 33 fish species in the Barents Sea in response to 10 environmental predictors. Boreal species are mainly limited by temperatures and most of them are expected to be able to expand their distribution in the Barents Sea when new thermally suitable habitats become available, in the limit of bathymetric constraints. Artic species are often limited by several predictors, mainly depth, bottom and surface temperature and ice cover, and future habitats are hard to predict qualitatively. Widespread species like the Atlantic cod are not strongly limited by the selected variables at the scale of the study, and current and future suitable habitats are harder to predict. These models can be used as input to integrative tools like end-to-end models on the habitat preference and tolerance at the species scale to inform resource management and conservation.
Description of a widespread bacterial secretion system with chemically diverse substrates
Authors: Grossman Alex S. , Mauer Terra J. , Forest Katrina T. , Goodrich-Blair Heidi
Published: January 2020

In host-associated bacteria, surface and secreted proteins mediate acquisition of nutrients, interactions with host cells, and specificity of tissue-localization. In Gram-negative bacteria, the mechanism by which many proteins cross or become tethered to the outer membrane remains unclear. Thedomain ofunknown function (DUF)560 occurs in outer membrane proteins throughout Proteobacteria and has been implicated in host-bacteria interactions and lipoprotein surface exposure. We used sequence similarity networking to reveal three subfamilies of DUF560 homologs. One subfamily includes those DUF560 proteins experimentally characterized to date: NilB, a host-range determinant of the nematode-mutualistXenorhabdus nematophila, and thesurface lipoproteinassemblymodulators Slam1 and Slam2, which facilitate msurface exposure of lipoproteins inNeisseria meningitidis(1, 2). We show that DUF560 proteins from a second subfamily facilitate secretion of soluble, non-lipidated proteins across the outer membrane. Usingin silicoanalysis, we demonstrate that DUF560 gene complement correlates with bacterial environment at a macro level and host association at a species level. The DUF560 protein superfamily represents a newly characterized Gram-negative secretion system capable of lipoprotein surface exposure and soluble protein secretion with conserved roles in facilitating symbiosis. In light of these data, we propose that it be titled the typeeleven secretionsystem (TXISS).

Importance

The microbial constituents of a host associated microbiome are decided by a complex interplay of microbial colonization factors, host surface conditions, and host immunological responses. Filling such niches requires bacteria to encode an arsenal of surface and secreted proteins to effectively interact with the host and co-occurring microbes. Bioinformatic predictions of the localization and function of putative bacterial colonization factors are essential for assessing the potential of bacteria to engage in pathogenic, mutualistic, or commensal activities. This study uses publicly available genome sequence data, alongside experimental results from representative gene products fromXenorhabdus nematophila, to demonstrate a role for DUF560 family proteins in the secretion of bacterial effectors of host interactions. Our research delineates a broadly distributed family of proteins and enables more accurate predictions of the localization of colonization factors throughout Proteobacteria.
Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex
Authors: Leandro João , Khamrui Susmita , Wang Hui , Suebsuwong Chalada , Nemeria Natalia S. , Huynh Khoi , Moustakim Moses , Secor Cody , Wang May , Dodatko Tetyana , Stauffer Brandon , Wilson Christopher G. , Yu Chunli , Arkin Michelle R. , Jordan Frank , Sanchez Roberto , DeVita Robert J. , Lazarus Michael B. , Houten Sander M.
Published: January 2020

DHTKD1 is the E1 component of the 2-oxoadipic acid dehydrogenase complex (OADHc), which functions in the L-lysine degradation pathway. Mutations inDHTKD1have been associated with 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth disease type 2Q (CMT2Q) and eosinophilic esophagitis (EoE). A crystal structure and inhibitors of DHTKD1 could improve the understanding of these clinically distinct disorders, but are currently not available. Here we report the identification of adipoylphosphonic acid and tenatoprazole as DHTKD1 inhibitors using targeted and high throughput screening, respectively. We furthermore elucidate the DHTKD1 crystal structure with thiamin diphosphate bound at 2.1 Å. The protein assembles as a dimer with residues from both monomers contributing to cofactor binding. We also report the impact of tenDHTKD1missense mutations on the encoded proteins by enzyme kinetics, thermal stability and structural modeling. Some DHTKD1 variants displayed impaired folding (S777P and S862I), whereas other substitutions rendered the enzyme inactive (L234G, R715C and R455Q) or affected the thermal stability and catalytic efficiency (V360A and P773L). Three variants (R163Q, Q305H and G729R) surprisingly showed wild type like properties. Our work provides a structural basis for further understanding of the function of DHTKD1 and a starting point for selective small molecule inhibitors of the enzyme, which could help tease apart the role of this enzyme in several human pathologies.
Fast Lasso method for Large-scale and Ultrahigh-dimensional Cox Model with applications to UK Biobank
Authors: Li Ruilin , Chang Christopher , Justesen Johanne Marie , Tanigawa Yosuke , Qian Junyang , Hastie Trevor , Rivas Manuel A. , Tibshirani Robert
Published: January 2020

We develop a scalable and highly efficient algorithm to fit a Cox proportional hazard model by maximizing theL1-regularized (Lasso) partial likelihood function, based on the Batch Screening Iterative Lasso (BASIL) method developed in (Qian et al. 2019). The output of our algorithm is the full Lasso path, the parameter estimates at all predefined regularization parameters, as well as their validation accuracy measured using the concordance index (C-index) or the validation deviance. To demonstrate the effectiveness of our algorithm, we analyze a large genotype-survival time dataset across 306 disease outcomes from the UK Biobank (Sudlow et al. 2015). Our approach, which we refer to as snpnet-Cox, is implemented in a publicly available package.
Discovery of a spatially and temporally persistent core microbiome of the common bean rhizosphere
Authors: Stopnisek Nejc , Shade Ashley
Published: January 2020

This manuscript has been withdrawn by the authors as it was submitted in error as a new manuscript rather than a revision ofhttps://doi.org/10.1101/727461. The authors do not wish for this preprint to be cited as reference for the project. Please instead seehttps://www.biorxiv.org/content/10.1101/727461v2for this version of the manuscript. Please contact the corresponding author if you have any questions.
The yeast mating-type switching endonuclease HO is a domesticated member of an unorthodox homing genetic element family
Authors: Coughlan Aisling Y. , Lombardi Lisa , Braun-Galleani Stephanie , Martos Alexandre A. R. , Galeote Virginie , Bigey Frédéric , Dequin Sylvie , Byrne Kevin P. , Wolfe Kenneth H.
Published: January 2020

The mating-type switching endonuclease HO plays a central role in the natural life cycle ofSaccharomyces cerevisiae, but its evolutionary origin is unknown.HOis a recent addition to yeast genomes, present in only a few genera. It resembles a degenerated intein fused to a zinc finger domain. Here we show thatHOis structurally and phylogenetically related to a family of unorthodox homing genetic elements found inTorulasporaandLachanceayeasts. TheseWHOelements integrate into the aldolase geneFBA1, replacing its 3’ end each time. Their structural organization is different from all known classes of homing elements. We show that a WHO protein cleavesTorulaspora delbrueckii FBA1efficiently and in an allele-specific manner, leading to DNA repair by gene conversion or NHEJ. The DNA rearrangement steps duringWHOelement homing are very similar to those during mating-type switching, and indicate thatHOis a domesticatedWHO-like element.
Effect of Perfluorooctanesulfonic acid (PFOS) on immune cell development and function in mice
Authors: Torres Luisa , Redko Amie , Limper Candice , Imbiakha Brian , Chang Sue , August Avery
Published: January 2020

Perfluorinated compounds, such as Perfluoroctane sulfonic acid (PFOS) are compounds containing carbon chains where hydrogens have been replaced with fluorines, and belong to a larger family known as Per- and polyfluoroalkyl substances (PFAS). The strength of the carbon–fluorine bond makes perfluorinated compounds extremely resistant to environmental degradation. Due to the persistent nature of PFOS, research has been directed to elucidating possible health effects of PFOS on humans and laboratory animals. Here we have explored the effects of PFOS exposure on immune development and function in mice. We exposed adult wild-type mice to 3 and 1.5 μg/kg/day of PFOS for 2 and 4 weeks, respectively, and examined the effects of PFOS exposure on populations of T cells, B cells, and granulocytes. These doses of PFOS resulted in serum levels of approximately 100 ng/ml with no weight loss during exposure. We find that PFOS does not affect T-cell development during this time. However, while PFOS exposure reduced immune cell populations in some organs, it also led to an increase in the numbers of cells in others, suggesting possible relocalization of cells. We also examined the effect of PFOS on the response to influenza virus infection. We find that exposure to PFOS at 1.5 μg/kg/day of PFOS for 4 weeks does not affect weight loss or survival, nor is viral clearance affected. Analysis of antibody and T cell specific antiviral responses indicate that at this concentration, PFOS does not suppress the immune cell development or antigen specific immune response.
How Sensitive are EEG Results to Preprocessing Methods: A Benchmarking Study
Authors: Robbins Kay A. , Touryan Jonathan , Mullen Tim , Kothe Christian , Bigdely-Shamlo Nima
Published: January 2020

Although several guidelines for best practices in EEG preprocessing have been released, even those studies that strictly adhere to those guidelines contain considerable variation in the ways that the recommended methods are applied. An open question for researchers is how sensitive the results of EEG analyses are to variations in preprocessing methods and parameters. To address this issue, we analyze the effect of preprocessing methods on downstream EEG analysis using several simple signal and event-related measures. Signal measures include recording-level channel amplitudes, study-level channel amplitude dispersion, and recording spectral characteristics. Event-related methods include ERPs and ERSPs and their correlations across methods for a diverse set of stimulus events. Our analysis also assesses differences in residual signals both in the time and spectral domains after blink artifacts have been removed. Using fully automated pipelines, we evaluate these measures across 17 EEG studies for two ICA-based preprocessing approaches (LARG, MARA) plus two variations of Artifact Subspace Reconstruction (ASR). Although the general structure of the results is similar across these preprocessing methods, there are significant differences, particularly in the low-frequency spectral features and in the residuals left by blinks. These results argue for detailed reporting of processing details as suggested by most guidelines, but also for using a federation of automated processing pipelines and comparison tools to quantify effects of processing choices as part of the research reporting.
Smchd1is a maternal effect gene required for autosomal imprinting
Authors: Wanigasuriya Iromi , Gouil Quentin , Kinkel Sarah A. , Tapia del Fierro Andrés , Beck Tamara , Roper Ellise E.A. , Breslin Kelsey , Stringer Jessica , Hutt Karla , Lee Heather J. , Keniry Andrew , Ritchie Matthew E. , Blewitt Marnie E.
Published: January 2020

Genomic imprinting establishes parental allele-biased expression of a suite of mammalian genes based on parent-of-origin specific epigenetic marks. These marks are under the control of maternal effect proteins supplied in the oocyte. Here we report the epigenetic repressorSmchd1as a novel maternal effect gene that regulates imprinted expression of 16 genes. Most Smchd1-sensitive genes only show loss of imprinting post-implantation, indicating maternal Smchd1’s long-lived epigenetic effect. Sm-chd1-sensitive genes include both those controlled by germline polycomb marks and germline DNA methylation imprints; however, Smchd1 differs to other maternal effect genes that regulate the latter group, as Smchd1 does not affect germline DNA methylation imprints. Instead, Smchd1-sensitive genes are united by their reliance on polycomb-mediated histone methylation marks as germline or secondary imprints. We propose that Smchd1 translates these imprints to establish a heritable chromatin state required for imprinted expression later in development, revealing a new mechanism for maternal effect genes.
scIGANs: single-cell RNA-seq imputation using generative adversarial networks
Authors: Xu Yungang , Zhang Zhigang , You Lei , Liu Jiajia , Fan Zhiwei , Zhou Xiaobo
Published: January 2020

Single-cell RNA-sequencing (scRNA-seq) enables the characterization of transcriptomic profiles at the single-cell resolution with increasingly high throughput. However, it suffers from many sources of technical noises, including insufficient mRNA molecules that lead to excess false zero values, termed dropouts. Computational approaches have been proposed to recover the biologically meaningful expression by borrowing information from similar cells in the observed dataset. However, these methods suffer from oversmoothing and removal of natural cell-to-cell stochasticity in gene expression. Here, we propose the generative adversarial networks (GANs) for scRNA-seq imputation (scIGANs), which uses generated cells rather than observed cells to avoid these limitations and balances the performance between major and rare cell populations. Evaluations based on a variety of simulated and real scRNA-seq datasets show that scIGANs is effective for dropout imputation and enhances various downstream analysis. ScIGANs is robust to small datasets that have very few genes with low expression and/or cell-to-cell variance. ScIGANs works equally well on datasets from different scRNA-seq protocols and is scalable to datasets with over 100,000 cells. We demonstrated in many ways with compelling evidence that scIGANs is not only an application of GANs in omics data but also represents a competing imputation method for the scRNA-seq data.
Phylogenetic relationships among haloalkaliphilic archaea of the familyNatrialbaceae
Authors: Siddaramappa Shivakumara
Published: January 2020

The familyNatrialbaceaeis a member of the classHalobacteriaof the archaeal phylumEuryarchaeota. Seventeen genera with validly or effectively published names are currently included within this family. In this study, using pairwise average nucleotide identity and average amino acid identity comparisons in conjunction with phylogenetic analysis, it has been shown that the familyNatrialbaceaeis highly diverse and contains several potentially novel species and genera that are yet to be fully characterized. The deduced proteome sequence-based phylogenetic tree, constructed using the alignment- and parameter-free method CVTree3, contained six major clades, withSalinarchaeumsp. Harcht-Bsk1 being the only representative within clade 1. Furthermore,Haloterrigena daqingensiswas found to be closely related toNatronorubrum sediminis, and it is proposed that these archaea together represent a novel genus. Interestingly,Haloterrigena jeotgali,Haloterrigena thermotolerans, andNatrinema pellirubrumwere found to be very closely related to each other, and it is proposed that they be merged into a single species. Notably, the type genusNatrialbaitself appeared to be heterogenous and contains species that could be broadly classified among two genera. Likewise, the genusNatrinemais also heterogenous and contains species that could be classified among six genera. Altogether, 19 novel genera have been proposed to be created, and four haloalkaliphilic archaea hitherto recognized only using genus names are confirmed to represent novel species.
Vegetation and seed bank dynamics highlight the importance of post-restoration management in sown grasslands
Authors: Valkó Orsolya , Deák Balázs , Török Péter , Tóth Katalin , Kiss Réka , Kelemen András , Miglécz Tamás , Sonkoly Judit , Tóthmérész Béla
Published: January 2020

Sowing grass seeds generally supports the rapid development of a closed perennial vegetation, which makes the method universally suitable for fast and effective landscape-scale restoration of grasslands. However, sustaining the recovered grasslands, and increasing their diversity is a challenging task. Understanding the role of seed bank compositional changes and vegetation dynamics contributes to designating management regimes that support the establishment of target species and suppress weeds. Our aim was to reveal the effect of post-restoration management on the vegetation and seed bank dynamics in grasslands restored in one of the largest European landscape-scale restoration projects. Eight years after restoration we sampled the vegetation and seed bank in a total of 96 plots located in 12 recovered grasslands in the Great Hungarian Plain. In each recovered grassland stand we designated a mown (mown from Year 1 to Year 8) and an abandoned sample site (mown from Year 1 to Year 3 then abandoned from Year 4 to Year 8). Mown and abandoned sites showed divergent vegetation and seed bank development. Abandonment led to the decline of sown grasses and higher cover of weeds, especially in the alkaline grasslands. Our study confirmed that seed bank has a limited contribution to the maintenance of biodiversity in both grassland types. We found that five years of abandonment had a larger effect on the seed bank than on the vegetation. We stress that long-term management is crucial for controlling the emergence of the weeds from their dense seed bank in restored grasslands.

Implications for practice

Seed sowing of grass mixtures can be a feasible tool for restoring grasslands at large scales. However, the developed vegetation usually has low biodiversity and a high seed density of weeds is typical in the soil seed bank even several years after the restoration. Therefore, post-restoration management is necessary for suppressing weeds both aboveground and belowground.

We recommend to design the long-term management of the sites subjected to grassland restoration already in the planning phase of the restoration projects and ensure that the management plan is ecologically and economically feasible.

We recommend to complement the monitoring of vegetation with the analysis of soil seed bank for evaluating restoration success.
Bioconjugation of AuNPs with HPV 16/18 E6 antibody through physical adsorption technique
Authors: Mwai Lucy Muthoni , Kyama Mutinda C. , Ngugi Caroline W. , Walong Edwin
Published: January 2020

Gold nanoparticle (AuNP) bioconjugates are increasingly being utilised in biomedicine due to their low toxicity on biological tissues and unique electronic and chemical properties. They have been utilised in several biological applications namely manufacture of nanomaterials, biosensing, electron microscopy and drug delivery systems. Particularly, immuno-assays often employ gold nanoparticles (AuNPs) to enhance detection of a biological component. This paper presents a study on the bioconjugation of AuNPs with Horse Radish Peroxidase conjugated Human Papilloma Virus 16/18 Early 6 antibodies (CIP5) against Early 6 (E6) oncoprotein that is overexpressed in cervical carcinoma progression through physical adsorption. This bioconjugate can be employed in diagnostic immunoassay for cervical cancer screening. The study also demonstrated that the antibody pI, gold colloidal solution pH and amount of antibody determine the generation of stable Antibody–AuNPs bioconjugates.
Patterns of DNA variation between the autosomes, the X chromosome and the Y chromosome inBos taurusgenome
Authors: Czech Bartosz , Guldbrandtsen Bernt , Szyda Joanna
Published: January 2020

The new ARS-UCD1.2 assembly of the bovine genome has considerable improvements. That might be assumed that a more accurate identification of patterns of genetic variation can be achieved with it. We explored differences in genetic variation between autosomes, the X chromosome, and the Y chromosome. In particular, densities of variants, annotation, lengths (only for InDels), nucleotide divergence, and Tajima’s D statistic between chromosomes. Whole-genome DNA sequences of 217 individuals representing different cattle breeds were examined. The analysis included the alignment to the new reference genome and variant calling. 23,655,295 SNPs and 3,758,781 InDels were detected. In contrast to autosomes, both sex chromosomes had negative values of Tajima’s D and lower nucleotide divergence. That implies a correlation between nucleotide diversity and recombination rate, which is obviously reduced for sex chromosomes. Moreover, accumulation of nonsynonymous mutations on the Y chromosome could be associated with loss of recombination. Also, the relatively lower effective population size for sex chromosomes leads to a lower expected density of variants.
Deciphering the Signaling Network Landscape of Breast Cancer Improves Drug Sensitivity Prediction
Authors: Tognetti Marco , Gabor Attila , Yang Mi , Cappelletti Valentina , Windhager Jonas , Charmpi Konstantina , de Souza Natalie , Beyer Andreas , Picotti Paola , Saez-Rodriguez Julio , Bodenmiller Bernd
Published: January 2020

Although genetic and epigenetic abnormalities in breast cancer have been extensively studied, it remains difficult to identify those patients who will respond to particular therapies. This is due in part to our lack of understanding of how the variability of cellular signaling affects drug sensitivity. Here, we used mass cytometry to characterize the single-cell signaling landscapes of 62 breast cancer cell lines and five lines from healthy tissue. We quantified 34 markers in each cell line upon stimulation by the growth factor EGF in the presence or absence of five kinase inhibitors. These data – on more than 80 million single cells from 4,000 conditions – were used to fit mechanistic signaling network models that provide unprecedented insights into the biological principles of how cancer cells process information. Our dynamic single-cell-based models more accurately predicted drug sensitivity than static bulk measurements for drugs targeting the PI3K-MTOR signaling pathway. Finally, we identified genomic features associated with drug sensitivity by using signaling phenotypes as proxies, including a missense mutation inDDIT3predictive of PI3K-inhibition sensitivity. This provides proof of principle that single-cell measurements and modeling could inform matching of patients with appropriate treatments in the future.

One-liner

Single-cell proteomics coupled to perturbations improves accuracy of breast tumor drug sensitivity predictions and reveals mechanisms of sensitivity and resistance.

HIGHLIGHTS

Mass cytometry study of signaling responses of 62 breast cancer cell lines and five lines from healthy tissue to EGF stimulation with or without perturbation with five kinase inhibitors.

Single-cell signaling features and mechanistic signaling network models predicted drug sensitivity.

Mechanistic signaling network models deepen the understanding of drug resistance and sensitivity mechanisms.

We identify drug sensitivity-predictive genomic features via proxy signaling phenotypes.
An anti-amyloidogenic treatment to specifically block the consolidation of traumatic events in mouse
Authors: López-García Paula , de Mingo Daniel Ramírez , McGreevy Kerry R. , Pallé Anna , Popiel Helena Akiko , Santi Andrea , Nagai Yoshitaka , Trejo José Luís , Carrión-Vázquez Mariano
Published: January 2020

Post-traumatic stress disorder (PTSD) is a mental health disorder triggered by the exposure to a traumatic event that manifests with anguish, intrusive memories and negative mood changes. So far, there is no efficient treatment for PTSD other than symptomatic palliative care. Based on the implication of the functional amyloid cytoplasmic polyadenylation element binding protein-3 (CPEB3) in the consolidation of memory, we propose its active amyloid state as a possible therapeutic target by blocking the consolidation of traumatic memories through polyglutamine binding peptide 1 (QBP1), an inhibitor of the amyloid oligomerization previously investigated inDrosophila.

To test this idea in mammals, here we have developed a transgenic mouse that constitutively expresses QBP1 peptide. We first assessed the innocuousness of this peptide for the normal development of the animal, which also showed normal locomotor activity and anxiety. By performing a battery of standard memory paradigms, we then showed that hippocampal-dependent and aversive memories were impaired in the QBP1 mice. Furthermore, protein expression in the hippocampi of experienced mice showed that QBP1 mice do not increase their levels of amyloid oligomerization, evincing the blockade of the CPEB3 protein in its inactive state. The ability of QBP1 to block aversive memories in mice represents the proof of concept of a novel pharmacological approach for prophylaxis and therapy of acute stress and post-traumatic stress disorders.
Single molecule analysis reveals the role of regulatory light chains in fine-tuning skeletal myosin-II function
Authors: Nayak Arnab , Wang Tianbang , Franz Peter , Steffen Walter , Chizhov Igor , Tsiavaliaris Georgios , Amrute-Nayak Mamta
Published: January 2020

Myosin II is the main force generating motor during muscle contraction. Myosin II exists as different isoforms, involved in diverse physiological functions. The outstanding question is whether the myosin heavy chain (MHC) isoforms alone account for the distinct physiological properties. Unique sets of essential and regulatory light chains (RLCs) assembled with specific MHCs raises an interesting possibility of specialization of myosin functions via light chains (LCs). Here, we ask whether different RLCs contribute to the functional diversification. To investigate this, we generated chimeric motors by reconstituting MHC fast isoform (MyHC-IId) and slow isoform (MHC-I) with different light chain variants. As a result of RLCs swapping, actin filament sliding velocity increased by ∼ 10 fold for the slow myosin and decreased by >3 fold for the fast myosin. Ensemble molecule solution kinetics and single molecule optical trapping measurements provided in-depth insights into altered chemo mechanical properties of the myosin motors, thereby affecting the sliding speed. We find that both slow and fast myosins mechanical output is sensitive to the RLC isoform and propose that RLCs are crucial in fine-tuning of the myosin function.
High Force Catch Bond Mechanism of Bacterial Adhesion in the Human Gut
Authors: Liu Zhaowei , Liu Haipei , Vera Andrés M. , Bernardi Rafael C. , Tinnefeld Philip , Nash Michael A.
Published: January 2020

Bacterial colonization of the human intestine requires firm adhesion of bacteria to insoluble targets under hydrodynamic flow. Here we report the molecular mechanism behind an mechanostable protein complex responsible for resisting high shear forces and adhering bacteria to cellulose fibers in the human gut. Using single-molecule force spectroscopy (SMFS), single-molecule FRET (smFRET), and molecular dynamics (MD) simulations, we resolved two binding modes and three unbinding reaction pathways of a mechanically ultrastableR. champanellensis(Rc) Dockerin-Cohesin (Doc-Coh) complex. The complex assembles in two discrete binding modes with significantly different mechanical properties, with one breaking at ~500 pN and the other at ~200 pN at loading rates from 1-100 nN/sec. A neighboring X-module domain allosterically regulates the binding interaction and inhibits one of the low-force pathways at high loading rates, giving rise to a new mechanism of catch bonding that manifests under force ramp protocols. Multi-state Monte Carlo simulations show strong agreement with experimental results, validating the proposed kinetic scheme. These results explain mechanistically how gut microbes regulate cell adhesion strength at high shear stress through intricate molecular mechanisms including dual-binding modes, mechanical allostery and catch bonds.
Deep learning based behavioral analysis enables high precision rodent tracking and is capable of outperforming commercial solutions
Authors: Sturman Oliver , von Ziegler Lukas , Schläppi Christa , Akyol Furkan , Grewe Benjamin , Bohacek Johannes
Published: January 2020

To study brain function, preclinical research relies heavily on animal monitoring and the subsequent analyses of behavior. Commercial platforms have enabled semi high-throughput behavioral analyses by providing accurate tracking of animals, yet they often struggle with the analysis of ethologically relevant behaviors and lack the flexibility to adapt to variable testing environments. In the last couple of years, substantial advances in deep learning and machine vision have given researchers the ability to take behavioral analysis entirely into their own hands. Here, we directly compare the performance of commercially available platforms (Ethovision XT14, Noldus; TSE Multi Conditioning System, TSE Systems) to cross-verified human annotation. To this end, we provide a set of videos - carefully annotated by several human raters - of three widely used behavioral tests (open field, elevated plus maze, forced swim test). Using these data, we show that by combining deep learning-based motion tracking (DeepLabCut) with simple post-analysis, we can track animals in a range of classic behavioral tests at similar or even greater accuracy than commercial behavioral solutions. In addition, we integrate the tracking data from DeepLabCut with post analysis supervised machine learning approaches. This combination allows us to score ethologically relevant behaviors with similar accuracy to humans, the current gold standard, thus outperforming commercial solutions. Moreover, the resulting machine learning approach eliminates variation both within and between human annotators. In summary, our approach helps to improve the quality and accuracy of behavioral data, outperforming commercial systems at a fraction of the cost.
Toxic effect of 2,2’-bis(bicyclo[2.2.1] heptane) on bacterial cells
Authors: Kessenikh A. G. , Yaguzhinsky L. S. , Bermeshev M. V. , Pevgov V. G. , Samoilov V. O. , Shorunov S. V. , Maksimov A. L. , Yaguzhinsky L. S. , Manukhov I. V.
Published: January 2020

Here we present the study of the genotoxic effect of a 2,2’-bis(bicyclo[2.2.1]heptane) (BBH), which is promising as a fuel component for liquid rocket engines. The use ofEscherichia coli lux-biosensors showed that in addition to DNA damage causing SOS-response, there is also an oxidative effect on cells. The greatest toxicity is determined by the mechanism of formation of superoxide anion radical and is detected by the lux biosensorE. colipSoxS-lux, in which the genes of bacterial luciferases are transcriptionally crosslinked with the promoter of thesoxSgene. It is assumed that the oxidation of BBH leads to the formation of reactive oxygen species, which should give the main contribution to the toxicity of this substance.
What causes different coronal curve patterns in idiopathic scoliosis?
Authors: Pasha Saba
Published: January 2020

Background

Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of the spinal column in otherwise healthy adolescents. The underlying mechanisms associated with the spinal deformity development have been explored which delineated the role of the sagittal curvature of the spine. The patterns of the spinal deformity vary between the AIS patients as shown in several classification systems. It remains to further investigate how variations in sagittal profiles result in different coronal plane deformities in AIS and how these deformation patterns are intrinsically different.

Methods

A total of 71 Lenke 1 and 52 Lenke 5 AIS patients were included retrospectively. The 3D models of the spine were generated from biplanar radiographs to calculate the clinical spinal parameters, vertebral axial rotations, and the 3D centerline of the spinal curvature. A classification based on the centerlines’ axial plane projection was developed. The 3D curvature of the centerline was calculated at each point. A 2D elastic rod finite element model (FEM) of the sagittal spinal curvature for each axial subtype was developed to calculate the 3D deformity of the spine under gravity and axial torsion. Differences in the axial clusters’ clinical parameters, curvature of the spine, and the deformation patterns of the FEM were compared. The characteristics of the sagittal curvature of these axial clusters were determined.

Results

Lenke1 was divided into two axial groups (I and II) whereas the Lenke 5 cohort all had the same axial projection pattern (loop shape). T5-T12 kyphosis was significantly different between Lenke1-Group I and the other two groups, p=0.04. The vertebral rotation in both Lenke1-Group I and Lenke 5 had only one maximum value and the FEM deformed in a loop shaped whereas Lenke1-group II showed two maximum values for vertebral rotation and the FEM of the centerline deformed in a lemniscate shape. The ratio of the spinal arc lengths above and below the sagittal inflection points for Lenke1-Groups I and II and Lenke 5 were 0.52, 1.16, and 3.24, respectively.

Conclusion

Variations in the axial plane projection of the curve were observed within Lenke types. Lenke 1- Group I and Lenke 5 showed similar 3D curve characteristics suggesting one 3D curve whereas Lenke1-Group II, with two 3D curves, behaved differently. The length of the spinal arcs above and below the sagittal inflection point related to the patterns of axial deformity.
Can early exposure to stress enhance resilience to ocean warming in two oyster species?
Authors: Pereira Roberta R. C. , Scanes Elliot , Gibbs Mitchell , Byrne Maria , Ross Pauline M.
Published: January 2020

Securing economically and ecologically significant molluscs, as our oceans warm and acidify due to climate change, is a global priority. South eastern Australia receives warm water in a strengthening East Australia Current and so resident species are vulnerable to elevated temperature and marine heat waves. This study tested whether oysters pre exposed to elevated temperature or heat stress enhances resilience to ocean warming later in life. Two Australian species, the flat oyster,Ostrea angasi,and the Sydney rock oyster,Saccostrea glomerata, were given a mild dose of warm water or “heat shock” stress in the laboratory and then transferred to elevated temperature conditions where we used the thermal outfall from power generation as a proxy to investigate the impacts of ocean warming. Shell growth, condition index, lipid content and profile and survival of oysters was impacted by elevated temperature in the field, with flat oysters being more impacted than Sydney rock oysters. Flat oysters grew faster than Sydney rock oysters at ambient temperature, but were more sensitive to elevated temperature. Early exposure to heat stress did little to ameliorate the negative effects of increased temperature, although the survival of heat shocked flat oysters was greater than non-heat shocked oysters. Further investigations are required to determine if early exposure to heat stress can act to inoculate oysters to future stress and overall enhance resilience of oysters to ocean warming.
Mitigating ecosystem impacts of bottom trawl fisheries for North Sea soleSolea soleaby replacing mechanical by electrical stimulation
Authors: Rijnsdorp A.D. , Depestele J. , Eigaard O.R. , Hintzen N.T. , Ivanovic A. , Molenaar P. , O’Neill F. , Polet H. , Poos J.J. , van Kooten T.
Published: January 2020

Ecosystem effects of bottom trawl fisheries are a major concern. We analysed whether the replacement of mechanical stimulation by electrical stimulation may reduce the adverse impacts on the benthic ecosystem in the beam trawl fishery for sole. Although the use of electricity is not allowed to catch fish in European Union waters, a number of beam trawlers got derogation and switched to pulse trawling to explore the potential to reduce impacts. We extended a recently developed assessment framework and showed that the switch to pulse trawling substantially reduced benthic impacts when exploiting the Total Allowable Catch of sole in the North Sea. We applied the framework to Dutch beam trawl logbook data from 2009 to 2017 and estimated that the trawling footprint decreased by 23%; the precautionary impact indicator of the benthic community decreased by 39%; the impact on median longevity decreased by 20%; the impact on benthic biomass decreased by 61%; the amount of sediment mobilised decreased by 39%. The decrease is due to the replacement of tickler chains by electrode arrays, a lower towing speed and higher catch efficiency for sole. The effort and benthic impact of the beam trawl fishery targeting plaicePleuronectes platessain the central North Sea increased with the recovery of the plaice stock. This study illustrates the usefulness of a standardized methodological framework to assess the differences in time trends and trawling impact between gears.
ADrosophilamodel of oral peptide therapeutics for adult Intestinal Stem Cell tumors
Authors: Bajpai Anjali , Ahmad Quazi Taushif , Tang Hong-Wen , Manzar Nishat , Singh Virender , Thakur Ashwani , Ateeq Bushra , Perrimon Norbert , Sinha Pradip
Published: January 2020

The proto-oncogene YAP /Yki, a transcription co-factor of the Hippo pathway, has been linked to many cancers. YAP interacts with DNA-binding TEAD/Sd proteins to regulate expression of its transcriptional targets. Disruption of YAP-TEAD therefore offers a potential therapeutic strategy. The mammalian Vestigial Like (VGLL) protein, specifically its TONDU domain, has been shown to competitively inhibit YAP-TEAD interaction and a TONDU peptide can suppress YAP-induced cancer. As TONDU could potentially be developed into a therapeutic peptide for multiple cancers, we evaluated its efficacy in Yki-driven adult Intestinal Stem Cell (ISC) tumors in Drosophila. We show that oral uptake of the TONDU peptide is highly effective at inhibiting Yki-driven gut tumors by suppressing YAP-TEAD interaction. Comparative proteomics of early and late stage Yki-driven ISC tumors revealed enrichment of a number of proteins, including members of the integrin signaling pathway, such as Talin, Vinculin and Paxillin. These, in turn displayed a decrease in their levels in TONDU-peptide treated tumors. Further, we show that Sd binds to the regulatory region of integrin-coding gene, mew, which codes for αPS1, a key integrin of the ISCs. In support to a possible role of integrins in Yki-driven ISC tumors, we show that genetic downregulation ofmewarrests Yki-driven ISC proliferation, reminiscent of the effects of TONDU peptide. Altogether, our findings present a novel platform for screening therapeutic peptides and provide insights into tumor suppression mechanisms.

SIGNIFICANCE STATEMENT

Discovering novel strategies to inhibit oncogene activity is a priority in cancer biology. As signaling pathways are widely conserved between mammals and Drosophila, these questions can be effectively addressed in this model organism. Here, we show that progression ofDrosophilaIntestinal Stem Cell (ISC) tumors induced by gain of an oncogenic form of the transcription co-factor Yki can be suppressed by feeding a peptide corresponding to the conserved TONDU domain of Vestigial (Vg), which blocks binding of Yki to the Sd transcription factor. Further, we show that down regulation of the integrin signaling pathway is causally linked to TONDU-peptide-mediated ISC tumor suppression. Our findings reveal thatDrosophilacan be successfully used to screen peptides for their therapeutic applications.
The photoreceptor UVR8 mediates the perception of both UV-B and UV-A wavelengths up to 350 nm of sunlight with responsivity moderated by cryptochromes
Authors: Rai Neha , O’Hara Andrew , Farkas Daniel , Safronov Omid , Ratanasopa Khuanpiroon , Wang Fang , Lindfors Anders V. , Jenkins Gareth I. , Lehto Tarja , Salojärvi Jarkko , Brosché Mikael , Strid Åke , Aphalo Pedro J. , Morales Luis O.
Published: January 2020

The photoreceptors UV RESISTANCE LOCUS 8 (UVR8) and CRYPTOCHROMES 1 and 2 (CRYs) play major roles in the perception of UV-B (280–315 nm) and UV-A/blue radiation (315–500 nm), respectively. However, it is poorly understood how they function in sunlight. The roles of UVR8 and CRYs were assessed in a factorial experiment withArabidopsis thalianawild-type and photoreceptor mutants exposed to sunlight for 6 h or 12 h under five types of filters with cut-offs in UV and blue-light regions. Transcriptome-wide responses triggered by UV-B and UV-A wavelengths shorter than 350 nm (UV-Asw) required UVR8 whereas those induced by blue and UV-A wavelengths longer than 350 nm (UV-Alw) required CRYs. UVR8 modulated gene expression in response to blue light while lack of CRYs drastically enhanced gene expression in response to UV-B and UV-Asw. These results agree with our estimates of photons absorbed by these photoreceptors in sunlight and within vitromonomerization of UVR8 by wavelengths up to 335 nm. Motif enrichment analysis predicted complex signaling downstream of UVR8 and CRYs. Our results highlight that it is important to use UV waveband definitions specific to plants’ photomorphogenesis as is routinely done in the visible region.