bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing the genetic basis of copper toxicity inDrosophilareveals a complex pattern of allelic, regulatory, and behavioral variation
Authors: Everman Elizabeth R. , Cloud-Richardson Kristen M. , Macdonald Stuart J.
Published: May 2020

A range of heavy metals are required for normal cell function and homeostasis. Equally, the anthropogenic release of heavy metals into soil and water sources presents a pervasive health threat. Copper is one such metal; it functions as a critical enzymatic cofactor, but at high concentrations is toxic, and can lead to the production of reactive oxygen species. Using a combination of quantitative trait locus (QTL) mapping and RNA sequencing in theDrosophilaSynthetic Population Resource (DSPR), we demonstrate that resistance to the toxic effects of ingested copper inD. melanogasteris genetically complex, and influenced by allelic and expression variation at multiple loci. Additionally, we find that copper resistance is impacted by variation in behavioral avoidance of copper and may be subject to life-stage specific regulation. Multiple genes with known copper-specific functions, as well as genes that are involved in the regulation of other heavy metals were identified as potential candidates to contribute to variation in adult copper resistance. We demonstrate that nine of 16 candidates tested by RNAi knockdown influence adult copper resistance, a number of which may have pleiotropic effects since they have previously been shown to impact the response to other metals. Our work provides new understanding of the genetic complexity of copper resistance, highlighting the diverse mechanisms through which copper pollution can negatively impact organisms. Additionally, we further support the similarities between copper metabolism and that of other essential and nonessential heavy metals.
Self-organization of cortical areas in the development and evolution of neocortex: a network growth model
Authors: Imam Nabil , Finlay Barbara
Published: May 2020

While the mechanisms generating the topographic organization of primary sensory areas in the neocortex are well-studied, what generates secondary cortical areas is virtually unknown. Using physical parameters representing primary and secondary visual areas as they vary from monkey to mouse, we derived a growth model to explore if characteristic features of secondary areas could be produced from correlated activity patterns arising from V1 alone. We found that V1 seeded variable numbers of secondary areas based on activity-driven wiring and wiring density limits within the cortical surface. These secondary areas exhibited the typical mirror-reversal of map topography on cortical area boundaries and progressive reduction of the area and spatial resolution of each new map on the caudorostral axis. Activity-based map formation may be the basic mechanism that establishes the matrix of topographically-organized cortical areas available for later computational specialization.
Evolutionary and homeostatic changes in morphology of visual dendrites of Mauthner cells inAstyanaxblind cavefish
Authors: Tanvir Zainab , Rivera Daihana , Severi Kristen E. , Haspel Gal , Soares Daphne
Published: May 2020

Mauthner cells are the largest neurons in the hindbrain of teleost fish and most amphibians. Each cell has two major dendrites thought to receive segregated streams of sensory input: the lateral dendrite receives mechanosensory input while the ventral dendrite receives visual input. These inputs, which mediate escape responses to sudden stimuli, may be modulated by the availability of sensory information to the animal. To understand the impact of the absence of visual information on the morphologies of Mauthner cells during development and evolutionary time scales, we examinedAstyanax mexicanus. This species of tetra is found in two morphs: a seeing surface fish and a blind cavefish. We compared the structure of Mauthner cells in surface fish raised under daily light conditions, surface fish that raised in constant darkness, and two independent lineages of cave populations. The length of ventral dendrites of Mauthner cells in dark-raised surface larvae were longer and more branched, while in both cave morphs the ventral dendrites were smaller or absent. The absence of visual input in surface fish with normal eye development leads to a homeostatic increase in dendrite size, whereas over evolution, the absence of light led to the loss of eyes and a phylogenetic reduction in dendrite size. Consequently, homeostatic mechanisms are under natural selection that provide adaptation to constant darkness.
Prediction of LncRNA Encoded Small Peptides in Glioma and The Oligomer Channel Functional Analysis Using in Silico Approaches
Authors: Cao Yipeng , Yang Rui , Lee Imshik , Zhang Wenwen , Sun Jiana , Wang Wei
Published: May 2020

Glioma is lethal malignant brain cancers, many reports have shown that abnormalities in the behavior of water and ion channels play an important role in regulating glioma proliferation, migration, apoptosis and differentiation. Recently, new studies have suggested that some long noncoding RNAs (lncRNAs) containing small open reading frames (smORFs), can encode small peptides and form oligomers for water or ion regulation. However, because these peptides are difficult to identify, their functional mechanisms are far from being clearly understood. In this study, we used bioinformatic methods and softwares to identify and evaluate lncRNAs in gliomas that may encode small transmembrane peptides. Combining ab initio homology modeling, molecular dynamics simulations and energetic calculations, we constructed a predictive model and predicted the oligomer channel activity of peptides by identifying the lncRNA ORFs.

We found that one key hub lncRNA, DLEU1, which contains two smORFs (ORF1 and ORF8) could encode small peptides that form pentameric channels. The mechanics of water and ion (Na + and Cl-) transport through this pentameric channel were simulated. The potential of mean force (PMF) of the H2O molecules along the two ORF-encoded peptide channels indicated that the energy barrier was different between ORF1 and ORF8. The ORF1-encoded peptide pentamer acted as a self-assembled water channel but not as an ion channel, and the ORF8 neither permeating ions nor water.

This work provides new methods and theoretical support for further elucidation of the function of lncRNA-encoded small peptides and their role in cancer. Additionally, it provides a theoretical basis for drug development.
BACPHLIP: Predicting bacteriophage lifestyle from conserved protein domains
Authors: Hockenberry Adam J. , Wilke Claus O.
Published: May 2020

Bacteriophages are broadly classified into two distinct lifestyles: temperate and virulent. Temperate phages are capable of a latent phase of infection within a host cell (lysogenic cycle), whereas virulent phages directly replicate and lyse host cells upon infection (lytic cycle). Accurate lifestyle identification is critical for determining the role of individual phage species within ecosystems and their effect on host evolution. Here, we present BACPHLIP, a BACterioPHage LIfestyle Predictor. BACPHLIP detects the presence of a set of conserved protein domains within an input genome and uses this data to predict lifestyle via a Random Forest classifier that was trained on a dataset of 634 phage genomes. On an independent test set of 423 phages, BACPHLIP has an accuracy of 98%, greatly exceeding that of the previously existing tools (79%). BACPHLIP is freely available on GitHub (https://github.com/adamhockenberry/bacphlip) and the code used to build and test the classifier is provided in a separate repository (https://github.com/adamhockenberry/bacphlip-model-dev) for users wishing to interrogate and re-train the underlying classification model.
Location Invariant Animal Recognition Using Mixed Source Datasets and Deep Learning
Authors: Shepley Andrew , Falzon Greg , Meek Paul , Kwan Paul
Published: May 2020

A time-consuming challenge faced by camera trap practitioners all over the world is the extraction of meaningful data from images to inform ecological management. The primary methods of image processing used by practitioners includes manual analysis and citizen science. An increasingly popular alternative is automated image classification software. However, most automated solutions are not sufficiently robust to be deployed on a large scale. Key challenges include limited access to images for each species and lack of location invariance when transferring models between sites. This prevents optimal use of ecological data and results in significant expenditure of time and resources to annotate and retrain deep learning models.

In this study, we aimed to (a) assess the value of publicly available non-iconic FlickR images in the training of deep learning models for camera trap object detection, (b) develop an out-of-the-box location invariant automated camera trap image processing solution for ecologist using deep transfer learning and (c) explore the use of small subsets of camera trap images in optimisation of a FlickR trained deep learning model for high precision ecological object detection.

We collected and annotated a dataset of images of “pigs” (Sus scrofaandPhacochoerus africanus)from the consumer image sharing website FlickR. These images were used to achieve transfer learning using a RetinaNet model in the task of object detection. We compared the performance of this model to the performance of models trained on combinations of camera trap images obtained from five different projects, each characterised by 5 different geographical regions. Furthermore, we explored optimisation of the FlickR model via infusion of small subsets of camera trap images to increase robustness in difficult images.

In most cases, the mean Average Precision (mAP) of the FlickR trained model when tested on out of sample camera trap sites (67.21-91.92%) was significantly higher than the mAP achieved by models trained on only one geographical location (4.42-90.8%) and rivalled the mAP of models trained on mixed camera trap datasets (68.96-92.75%). The infusion of camera trap images into the FlickR training further improved AP by 5.10-22.32% to 83.60-97.02%.

Ecology researchers can use FlickR images in the training of automated deep learning solutions for camera trap image processing to significantly reduce time and resource expenditure by allowing the development of location invariant, highly robust out-of-the-box solutions. This would allow AI technologies to be deployed on a large scale in ecological applications.
Gene Editing Reveals Obligate and Modulatory Components of the CO2Receptor Complex in the Malaria Vector Mosquito,Anopheles coluzzii
Authors: Liu Feng , Ye Zi , Baker Adam , Sun Huahua , Zwiebel Laurence J.
Published: May 2020

The sensitivity to volatile carbon dioxide (CO2) produced by humans and other animals is a critical component in the host preference behaviors of the malaria vector mosquitoAnopheles coluzzii. The molecular receptors responsible for the ability to sense CO2are encoded by three putative gustatory receptor (Gr) genes (Gr22,23,24) which are expressed in a distinctive array of sensory neurons housed in maxillary palp capitate peg sensilla ofAn. coluzzii. Despite the identification of these components and subsequent studies, there is a paucity of understanding regarding the respective roles of these three GRs in the mosquito’s CO2transduction process. To address this, we have used CRISPR/Cas9-based gene editing techniques combined within vivoelectrophysiological recordings to directly examine the role ofGr22,23,24in detecting CO2inAn. coluzzii. These studies reveal that bothGr23andGr24are absolutely required to maintainin vivoCO2sensitivity while, in contrast,Gr22knock out mutants are still able to respond to CO2stimuli albeit with significantly weaker sensitivity. Our data supports a model in whichGr22plays a modulatory role to enhance the functionality ofGr23/24complexes that are responsible for CO2sensitivity of mosquitoes.
STING deficiency-associated aberrant CXCL10 expression contributes to pathogenesis of arthritogenic alphaviruses
Authors: Lin Tao , Geng Tingting , Harrison Andrew , Yang Duomeng , Vella Anthony T. , Fikrig Erol , Wang Penghua
Published: May 2020

Arthritogenic alphaviruses such as Chikungunya virus and O’nyong nyong virus cause acute and chronic crippling arthralgia associated with inflammatory immune responses. However, the physiological functions of individual immune signaling pathways in the pathogenesis of alphaviral arthritis remain poorly understood. Here we report that a deficiency in the stimulator-of-interferon-genes (STING) led to enhanced viral loads, exacerbated inflammation and selectively elevated expression of CXCL10, a chemoattractant for monocytes/macrophages/T cells, in mouse feet.Cxcl10-/-mice had the same viremia as wild-type animals, but fewer immune infiltrates and lower viral loads in footpads at the peak of arthritic disease (6-8 days post infection). Macrophages constituted the largest immune cell population in footpads following infection, which were significantly reduced inCxcl10-/-mice. The viral RNA loads in neutrophils and macrophages were reduced inCxcl10-/-compared to wild-type mice. In summary, our results demonstrate that STING signaling represses, while CXCL10 signaling promotes, pathogenesis of alphaviral disease.
Integrin αvβ8 on T cells is responsible for suppression of anti-tumor immunity in multiple syngeneic models and is a promising target for tumor immunotherapy
Authors: Dodagatta-Marri Eswari , Ma Hsiao-Yen , Liang Benjia , Li John , Meyer Dominique S. , Sun Kai-Hui , Ren Xin , Zivak Bahar , Rosenblum Michael D. , Headley Mark B. , Pinzas Lauren , Reed Nilgun I. , Del Cid Joselyn S. , Adoumie Maeva , Hann Byron C. , Yang Sharon , Giddabasappa Anand , Noorbehesht Kavon , Yang Bing , Dal Porto Joseph , Tsukui Tatsuya , Niessen Kyle , Atakilit Amha , Akhurst Rosemary J. , Sheppard Dean
Published: May 2020

The αvβ8 integrin is a key activator of transforming growth factor β (TGF β), which has been shown to inhibit anti-tumor immunity. Previous work has suggested that αvβ8 on tumor cells could modulate tumor growth and responses to immune checkpoint blockade. We now show that a potent blocking monoclonal antibody against αvβ8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma (CCK168), mammary cancer (EMT-6), colon cancer (CT26), and prostate cancer (TRAMPC2), especially when it is combined with other immunomodulators (anti-PD-1, anti-CTLA-4 or 4-1BB) or radiotherapy. αvβ8 is expressed on tumor cells in some of these models, but tumor cell expression of αvβ8 is not essential for the beneficial effects of ADWA-11 therapy. αvβ8 is consistently expressed at highest levels on CD4+CD25+ T cells within tumors, and specific deletion ofItgb8from T cells is as effective as ADWA-11 in suppressing tumor growth. Treatment with ADWA-11 increases expression of a suite of genes in tumor infiltrating CD8+ T cells that are normally inhibited by TGFβ and are involved in tumor cell killing, including Granzyme B and Interferon-γ. These findings solidify αvβ8 integrin as a promising target for cancer immunotherapy, even for tumors that do not express this integrin.
A simple method for gene expression in endo- and ectodermal cells in mouse embryos before neural tube closure
Authors: Kishi Yusuke , Maeda Yurie , Kuwayama Naohiro , Gotoh Yukiko
Published: May 2020

The lack of a widely accessible method for expressing genes of interest in wild-type embryos is the fundamental obstacle in understanding genetic regulation during embryonic development. In particular, only a few methods are available for introducing gene expression vectors into cells prior to neural tube closure, a period for the drastic development of many tissues. In this study, we present a simple technique for transferring vectors into the endo- and ectodermal cells of mouse embryos at E7.0 or E8.0 via in utero injection, without any specialized equipment. Using this technique, introduction of retroviruses can facilitate the labeling of cells in various tissues, including the brain, spinal cord, epidermis, and digestive and respiratory organs. As such, this technique can aid in analyzing the roles of genes of interest during endo- and ectodermal development prior to neural tube closure.
Endogenous formaldehyde scavenges cellular glutathione resulting in cytotoxic redox disruption
Authors: Umansky Carla , Morellato Agustín , Scheidegger Marco , Rieckher Matthias , Martinefski Manuela R. , Fernandez Gabriela A. , Kolesnikova Ksenia , Vesting Anna J. , Karakasilioti Ismene , Reingruber Hernán , Wei Yan , He Rongqiao , Bollini Mariela , Monge María Eugenia , Schumacher Björn , Pontel Lucas B.
Published: May 2020

Formaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking. We show here that FA can cause cellular damage beyond genotoxicity by triggering oxidative stress, which is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR). Mechanistically, we determine that endogenous FA reacts with the redox-active thiol group of glutathione (GSH) forming S-hydroxymethyl-GSH, which is metabolized by ADH5 yielding reduced GSH thus preventing redox disruption. We identify theADH5-ortholog gene inCaenorhabditis elegansand show that oxidative stress also underlies FA toxicity in nematodes. Moreover, we show that endogenous GSH can protect cells lacking the Fanconi Anemia DNA repair pathway from FA, which might have broad implications for Fanconi Anemia patients and for healthyBRCA2-mutation carriers. We thus establish a highly conserved mechanism through which endogenous FA disrupts the GSH-regulated cellular redox homeostasis that is critical during development and aging.
Transparency in butterflies and moths: structural diversity, optical properties and ecological relevance
Authors: Gomez D. , Pinna C. , Pairraire J. , Arias M. , Barbut J. , Pomerantz A. , Noûs C. , Daney de Marcillac W. , Berthier S. , Patel N. , Andraud C. , Elias M.
Published: May 2020

In water, transparency seems an ideal concealment strategy, as testified by the variety of transparent aquatic organisms. By contrast, transparency is nearly absent on land, with the exception of insect wings, and knowledge is scarce about its functions and evolution, with fragmentary studies and no comparative perspective. Lepidoptera (butterflies and moths) represent an outstanding group to investigate transparency on land, as species typically harbour opaque wings covered with coloured scales, a key multifunctional innovation. Yet, many Lepidoptera species have evolved partially or fully transparent wings. At the interface between physics and biology, the present study investigates transparency in 123 Lepidopteran species (from 31 families) for its structural basis, optical properties and biological relevance in relation to thermoregulation and vision. Our results establish that transparency has likely evolved multiple times independently. Efficiency at transmitting light is largely determined by clearwing microstructure (scale shape, insertion, colouration, dimensions and density) and macrostructure (clearwing area, species size or wing area). Microstructural traits – density, dimensions – are tightly linked in their evolution, with different constraints according to scale shape, insertion, and colouration. Transparency appears highly relevant for vision, especially for camouflage, with size-dependent and activity-rhythm dependent variations. Links between transparency and latitude are consistent with an ecological relevance of transparency in thermoregulation, and not so for protection against UV radiation. Altogether, our results shed new light on the physical and ecological processes driving the evolution of transparency on land and underline that transparency is a more complex than previously thought colouration strategy.
Phagosome resolution regenerates lysosomes and maintains the degradative capacity in phagocytes
Authors: Lancaster Charlene , Fountain Aaron , Dayam Roaya M. , Somerville Elliott , Sheth Javal , Jacobelli Vanessa , Somerville Alex , Terebiznik Mauricio , Botelho Roberto J.
Published: May 2020

Phagocytes engulf unwanted particles into phagosomes that then fuse with lysosomes to degrade the enclosed particles. Ultimately, phagosomes must be recycled to help recover membrane resources that were consumed during phagocytosis and phagosome maturation, a process referred to as phagosome resolution. Little is known about phagosome resolution, which may proceed through exocytosis or membrane fission. Here, we show that bacteria-containing phagolysosomes in macrophages undergo fragmentation through vesicle budding, tubulation, and constriction. Phagosome fragmentation requires cargo degradation, the actin and microtubule cytoskeletons, and clathrin. We provide evidence that lysosome reformation occurs during phagosome resolution since the majority of phagosome-derived vesicles displayed lysosomal properties. Importantly, we show that clathrin-dependent phagosome resolution is important to maintain the degradative capacity of macrophages challenged with two waves of phagocytosis. Overall, our work suggests that phagosome resolution contributes to lysosome recovery and to maintain the degradative power of macrophages to handle multiple waves of phagocytosis.

Phagocytes engulf particles into phagolysosomes for degradation. However, the ultimate fate of phagolysosomes is undefined. Lancaster, Fountain et al. show that phagosomes fragment to reform lysosomes in a clathrin-dependent manner. This process helps maintain the degradative capacity of phagocytes for subsequent rounds of phagocytosis.
Multiple domains in ARHGAP36 regulate PKA degradation and Gli activation
Authors: Nano Patricia R. , Kudo Takamasa , Mooney Nancie A. , Ni Jun , Demeter Janos , Jackson Peter K. , Chen James K.
Published: May 2020

ARHGAP36 is a Rho GTPase-activating protein (GAP) family member that contributes to spinal cord development and tumorigenesis. This multidomain protein is composed of splicing-dependent N-terminal sequences, the GAP-like region, and a unique C-terminal domain, and an N-terminal arginine-rich region has been shown to suppress protein kinase A (PKA) and activate Gli transcription factors. To understand how these structural elements act in concert, we have mapped the ARHGAP36 structure-activity landscape with domain- and amino-acid-level resolution. ARHGAP36-mediated Gli activation can be repressed by N-terminal sequences that regulate subcellular ARHGAP36 localization and PKA targeting. The GAP-like and C-terminal domains counteract this autoinhibitory mechanism and promote ARHGAP36 trafficking to the plasma membrane and primary cilium, respectively. The GAP-like domain may also conditionally suppress the arginine-rich region, and it modulates ARHGAP36 binding to the prolyl oligopeptidase-like protein PREPL and the E3 ubiquitin ligase PRAJA2. These domain-dependent activities provide a potential means for tissue-specific ARHGAP36 functions.
HBV pgRNA can generate a circRNA with two junction sites
Authors: Zhu Min , Liang Zi , Pan Jun , Hu Xiaolong , Zhang Xing , Xue Renyu , Cao Guangli , Gong Chengliang
Published: May 2020

To verify whether Hepatitis B virus (HBV) can form circRNA, the circRNA sequencing results of the HBV-positive HepG 2.2.15 hepatocarcinoma cell line were compared with the HBV genome. A novel circRNA, named as HBV_circ_1, was mapped to the 489–2985 nt region of the HBV genome (GenBank accession No.KU668446.1), which was derived from HBV pgRNA and has two junction sites. A partial fragment of the pgRNA (corresponding to HBV DNA genome 489-3,182-2,985nt) was resected and then connected to form a junction site of HBV_circ_1 (corresponding to HBV DNA genome 489/2985nt). The 5’-terminal region (corresponding to HBV DNA genome 1,820-1,932nt) of pgRNA was repeated with the region of pgRNA at the 3’-terminal region. Another junction site of HBV_circ_1 (corresponding to HBV DNA genome 1820nt) was formed in a manner similar to DNA homologous recombination mediated by repeats of pgRNA. Moreover, this RNA homologous recombination mediated by the repeats of pgRNA does not have tissue specificity and genus specificity. Reverse transcription PCR, northern blotting, and tissue in situ hybridization confirmed the existence of HBV_circ_1 in HepG2.2.15 cells and HBV related hepatocellular carcinoma (HCC) tissue. This study expands our understanding of circRNA generation mechanisms, and provide a new perspective for understanding the molecular pathogenesis of the virus.
Interval Constraint Satisfaction and Optimization for Biological Homeostasis and Multistationarity
Authors: Desoeuvres Aurélien , Trombettoni Gilles , Radulescu Ovidiu
Published: May 2020

Homeostasisoccurs in a biological or chemical system when some output variable remains approximately constant as one or several input parameters change over some intervals. We propose in this paper a new computational method based on interval techniques to find species in biochemical systems that verify homeostasis. A somehow dual and equally important property ismultistationarity, which means that the system has multiple steady states and possible outputs, at constant parameters. We also propose an interval method for testing multistationarity. We have tested homeostasis, absolute concentration robustness and multistationarity on a large collection of biochemical models from the Biomodels and DOCSS databases. The codes used in this paper are publicly available at:https://github.com/Glawal/IbexHomeo.
Single-cell RNA-seq reveals lineage-specific regulatory changes of fibroblasts and vascular endothelial cells in keloid
Authors: Liu Xuanyu , Chen Wen , Yuan Meng , Li Zhujun , Meng Tian , Chen Jie , Yu Nanze , Long Xiao , Zhou Zhou
Published: May 2020

Keloid is a benign dermal fibrotic disorder with some features similar to malignant tumors such as hyper-proliferation, apoptosis resistance and invasion. keloid remains a therapeutic challenge in terms of high recurrence rate and lack of satisfactory medical therapies, which is partially due to the incomplete understanding of keloid pathogenesis. A thorough understanding of the cellular and molecular mechanism of keloid pathogenesis would facilitate the development of novel medical therapies for this disease. Here, we performed single-cell RNA-seq of 28,064 cells from keloid skin tissue and adjacent relatively normal tissue. Unbiased clustering revealed substantial cellular heterogeneity of the keloid tissue, which included 21 cell clusters assigned to 11 cell lineages. Differential proportion analysis revealed significant expansion for fibroblasts and vascular endothelial cells in keloid compared with control, reflecting their strong association with keloid pathogenesis. We then identified five previously unrecognized subpopulations of keloid fibroblasts and four subpopulations of vascular endothelial cells. Comparative analyses were performed to identify the dysregulated pathways, regulators and ligand-receptor interactions for keloid fibroblasts and vascular endothelial cells, the two important cell lineages in keloid pathogenesis and for medical interventions. Our results highlight the roles of transforming growth factor beta and Eph-ephrin signaling pathways in both the aberrant fibrogenesis and angiogenesis of keloid. Critical regulators and signaling receptors implicated in the fibrogenesis of other fibrotic disorders, such asTWIST1, FOXO3, SMAD3andEPHB2, ranked at the top in the regulatory network of keloid fibroblasts. In addition, tumor-related pathways such as negative regulation ofPTENtranscription were found to be activated in keloid fibroblasts and vascular endothelial cells, which may be responsible for the malignant features of keloid. Our study put novel insights into the pathogenesis of keloid, and provided potential targets for medical therapies. Our dataset also constitutes a valuable resource for further investigations of the mechanism of keloid pathogenesis.
The weakly electric fish,Apteronotus albifrons, avoids hypoxia before it reaches critical levels
Authors: Mucha Stefan , Chapman Lauren J. , Krahe Rüdiger
Published: May 2020

Anthropogenic environmental degradation has led to an increase in the frequency and prevalence of aquatic hypoxia (low dissolved-oxygen concentration, DO), which may affect habitat quality for water-breathing fishes. The weakly electric black ghost knifefish,Apteronotus albifrons, is typically found in well-oxygenated freshwater habitats in South America. Using a shuttle-box design, we exposed juvenileA. albifronsto a stepwise decline in DO from normoxia (>95% air saturation) to extreme hypoxia (10% air saturation) in one compartment and chronic normoxia in the other. Below 22% air saturation,A. albifronsactively avoided the hypoxic compartment. Hypoxia avoidance was correlated with upregulated swimming activity. Following avoidance, fish regularly ventured back briefly into deep hypoxia. Hypoxia did not affect the frequency of their electric organ discharges. Our results show thatA. albifronsis able to sense hypoxia at non-lethal levels and uses active avoidance to mitigate its adverse effects.

The weakly electric knifefish,Apteronotus albifrons, avoids hypoxia below 22% air saturation. Avoidance correlates with increased swimming activity, but not with a change in electric organ discharge frequency.
Identifying Behavioral Structure from Deep Variational Embeddings of Animal Motion
Authors: Luxem Kevin , Mocellin Petra , Fuhrmann Falko , Kürsch Johannes , Remy Stefan , Bauer Pavol
Published: May 2020

Abstract

Quantification and detection of the hierarchical organization of behavior is a major challenge in neuroscience. Recent advances in markerless pose estimation enable the visualization of highdimensional spatiotemporal behavioral dynamics of animal motion. However, robust and reliable technical approaches are needed to uncover underlying structure in these data and to segment behavior into discrete hierarchically organized motifs. Here, we present an unsupervised probabilistic deep learning framework that identifies behavioral structure from deep variational embeddings of animal motion (VAME). By using a mouse model of beta amyloidosis as a use case, we show that VAME not only identifies discrete behavioral motifs, but also captures a hierarchical representation of the motif’s usage. The approach allows for the grouping of motifs into communities and the detection of differences in community-specific motif usage of individual mouse cohorts that were undetectable by human visual observation. Thus, we present a novel and robust approach for quantification of animal motion that is applicable to a wide range of experimental setups, models and conditions without requiring supervised or a-priori human interference.
Modeling the IL-2-Teff-Treg system in Systemic Lupus Erythematosus patients: possible mechanism and treatment strategies
Authors: Gao Xin , Sun Xiaolin , He Jing , Li Fangting
Published: May 2020

Systemic lupus erythematosus (SLE) is a non-organ specific autoimmune disease, which the pathogenesis of development is still unclear. For revealing the underlying mechanism, we construct a mathematical model depicting the interactions among CD4+regulatory T cells (Treg cells), CD4+effect T cells (Teff cells) and IL-2 in SLE patients to simulate and reproduce the development of SLE. Through our analysis, one possible pathogenesis is that the activation point and deactivation point of Teff in SLE patients produced a forward shift compared to the normal Teff. According to our simulation, a therapeutic window existed in the treatment of lupus with exogenous IL-2, which means there is a strict limit to the dose of IL-2 in clinic. Finally, we study three different dosing strategies and reveal that specific dosing regimens can better exert the effects of IL-2 and relieve the possible side effect of high dose IL-2. It is possible to promote the study of autoimmune diseases through our efforts and assist the development of precision medical treatment.
Artificial neural networks for monitoring network optimisation—a practical example using a national insect survey
Authors: Bourhis Yoann , Bell James R. , van den Bosch Frank , Milne Alice E.
Published: May 2020

Monitoring networks are improved by additional sensors. Optimal configurations of sensors give better representations of the process of interest, maximising its exploration while minimising the need for costly infrastructure. By modelling the monitored process, we can identify gaps in its representation,i.e.uncertain predictions, where additional sensors should be located. Here, with data collected from the Rothamsted Insect Survey network, we train an artificial neural network to predict the seasonal aphid arrival from environmental variables. We focus on estimating prediction uncertainty across the UK to guide the addition of a sensor to the network. We first illustrate how to estimate uncertainty in neural networks, hence making them relevant for model-based monitoring network optimisation. Then we highlight critical areas of agricultural importance where additional traps would improve decision support and crop protection in the UK. Possible applications include most ecological monitoring and surveillance activities, but also the weather or pollution monitoring.
Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis
Authors: Christodoulou-Vafeiadou Eleni , Geka Christina , Ntari Lydia , Kranidioti Ksanthi , Argyropoulou Eleni , Meier Florian , Armaka Marietta , Mourouzis Iordanis , Pantos Constantinos , Rouchota Maritina , Loudos George , Denis Maria C , Karagianni Niki , Kollias George
Published: May 2020

Background

The transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis we performed detailed characterization of the axial, peripheral and comorbid pathologies of this model.

Methods

TgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by µCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically and by µCT analysis.

Results

TgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings as well as swollen and distorted hind joints. Whole body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limps, and also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice.

Conclusions

The TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall faithfully reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.
Genome-wide association analysis and replication in 810,625 individuals identifies novel therapeutic targets for varicose veins
Authors: Ahmed Waheed-Ul-Rahman , Wiberg Akira , Ng Michael , Wang Wei , Auton Adam ,   23andMe Research Team, Lee Regent , Handa Ashok , Zondervan Krina T , Furniss Dominic
Published: May 2020

Background

Varicose veins (VVs) affect one-third of Western society, with a significant subset of patients developing venous ulceration, and ongoing management of venous leg ulcers costing around $14.9 billion annually in the USA. There is no current medical management for VVs, with approaches limited to compression stockings, ablation techniques, or open surgery for more advanced disease. A significant proportion of patients report a positive family history, and heritability is ~17%, suggesting a strong genetic component. We aimed to identify novel therapeutic targets by improving our understanding of the aetiopathology and genetic architecture of VVs.

Methods

We performed the largest two-stage genome-wide association study of VVs in 401,656 subjects from UK Biobank, and replication in 408,969 subjects from 23andMe (total 135,514 varicose veins cases and 675,111 controls). We constructed a genetic risk score for VVs to investigate its use as a prognostic tool. Genes and pathways were prioritised using a suite of bioinformatic tools, and therapeutic targets identified using the Open Targets Platform.

Results

We discovered 49 signals at 46 susceptibility loci associated with VVs, including 29 previously unreported genetic associations (28 susceptibility loci). We demonstrated that patients with VVs requiring surgery have a higher genetic risk score than those managed non-surgically. We map 237 genes to these loci, many of which are biologically relevant and tractable to therapeutic targeting or repurposing (notablyVEGFA,COL27A1,EFEMP1,PPP3R1andNFATC2). Tissue enrichment analyses implicated vascular tissue, and several genes were enriched in biological pathways relating to extracellular matrix biology, inflammation, angiogenesis, lymphangiogenesis, vascular smooth muscle cell migration, and apoptosis.

Conclusions

Genes and pathways identified represent biologically plausible contributors to the pathobiology of VVs, identifying promising candidates for further investigation of venous biology and potential therapeutic targets. We have provided the proof-of-principle that genetic risk score correlates with disease severity, which represents a first step in personalised medicine approaches to varicose veins.
Advanced Research Infrastructure for Experimentation in genomicS (ARIES): a lustrum of Galaxy experience
Authors: Knijn Arnold , Michelacci Valeria , Orsini Massimiliano , Morabito Stefano
Published: May 2020

Background: With the introduction of Next Generation Sequencing (NGS) and Whole-Genome Sequencing (WGS) in microbiology and molecular epidemiology, the development of an information system for the collection of genomic and epidemiological data and subsequent transparent and reproducible data analysis became indispensable. Further requirements for the system included accessibility and ease of use by bioinformatics as well as command line profane scientists.

Findings: The ARIES (Advanced Research Infrastructure for Experimentation in genomicS,https://aries.iss.it) platform has been implemented in 2015 as an instance of the Galaxy framework specific for use of WGS in molecular epidemiology. Here, the experience with ARIES is reported. Conclusions: During its five years existence, ARIES has grown into a well-established reality not only as a web service but as well as a workflow engine for the Integrated Rapid Infectious Disease Analysis (IRIDA) platform. In fact, an environment has been created with the implementation of complex bioinformatic tools in an easy-to-use context allowing scientists to concentrate on what to do instead of how to do it.
The response of zinc transporter gene expression of selected tissues in a pig model of subclinical zinc deficiency
Authors: Brugger Daniel , Hanauer Martin , Ortner Johanna , Windisch Wilhelm M.
Published: May 2020

This study compared the relative mRNA expression of all mammal zinc (Zn) transporter genes in selected tissues of weaned piglets challenged with short-term subclinical Zn deficiency (SZD). The dietary model involved restrictive feeding (450 g/animal*day−1) of a high-phytate diet (9 g/kg) supplemented with varying amounts of zinc from ZnSO4*7H2O ranging from deficient to sufficient supply levels (total diet Zn: 28.1, 33.6, 38.8, 42.7, 47.5, 58.2, 67.8, 88.0 mg Zn/kg). Total RNA preparations comprised jejunal and colonic mucosa as well as hepatic and nephric tissue. Statistical modelling involved broken-line regression (P ≤ 0.05). ZIP10 and ZIP12 mRNAs were not detected in any tissue and ZnT3 mRNA was only identified in the kidney. All other genes were expressed in all tissues but only a few gene expression patterns allowed a significant (P < 0.0001) fitting of broken-line regression models, indicating homeostatic regulation under the present experimental conditions. Interestingly, these genes could be subcategorized by showing significant turnarounds in their response patterns, either at ~40 or ~60 mg Zn/kg diet (P < 0.0001). In conclusion, the present study showed clear differences in Zn transporter gene expression in response to SZD compared to the present literature on clinical models. We recognized that certain Zn transporter genes were regulated under the present experimental conditions by two distinct homeostatic networks. For the best of our knowledge, this represents the first comprehensive screening of Zn transporter gene expression in a highly translational model to human physiology.
Mediterranean oaks harbor more specific soil microbes at the dry end of a precipitation gradient
Authors: Rutten Gemma , Gómez-Aparicio Lorena , Frey Beat
Published: May 2020

Background

Recent evidence suggests that soil microbial communities can regulate plant community dynamics. In addition, the drought tolerance of plants can be enhanced by soil microbes. So far, few studies have assessed the variation in the microbiome of specific plant species along environmental gradients. Yet understanding these dynamics is essential to improve predictions of plant-soil feedbacks and the consequences of ongoing climate changes. Here we characterized the soil microbiome of two co-occurring Mediterranean oaks along a precipitation gradient, using amplicon sequencing of phylogenetic marker genes for prokaryotes and fungi. Additionally, we identified tree-specific and locally-specific microbes potentially responsible for tree community dynamics.

Results

We show that two co-occurring, evergreen Mediterranean oak species harbor distinct microbiomes along a precipitation gradient. The soil microbial diversity increased along the precipitation gradient, for prokaryotic α and β diversity and for fungal β diversity.Quercus ilexharbored richer fungal communities thanQuercus suber, and host-specific taxa more often belonged to fungi than to prokaryotes. Notably, the microbial communities at the dry end of the precipitation gradient harbored more locally-specific prokaryotic and fungal taxa than the microbial communities with a higher diversity, at the wet end of the gradient, suggesting higher specialization in drier areas.

Conclusions

Even congeneric tree species, belonging to the same functional group, can harbor distinct and specific soil microbiomes. These microbiomes become more similar and consist of more specialized taxa under drier compared with wetter conditions. With this, our study offers a step towards a better understanding of the context-dependency of plant-soil feedbacks by going beyond α and β diversities and focusing on specialized taxa potentially driving community changes along environmental gradients. We hope that our study will stimulate future research assessing the importance of context-dependency of interactions between plants and soil communities in a changing world.
Recurrent evolution of two competing haplotypes in an insect DNA virus
Authors: Hill Tom , Unckless Robert L.
Published: May 2020

Hosts and viruses are constantly evolving in response to each other: as hosts attempt to suppress the virus, the virus attempts to evade and suppress the host’s immune system. This arms race results in the evolution of novel pathways in both the host and virus to gain the upper hand. Here we describe the coevolution betweenDrosophilaspecies and a common and virulent DNA virus. We identify two distinct viral types that differ 100-fold in viral titer in infected individuals, with similar effects across multiple species. Our analysis suggests that one of the viral types appears to have recurrently evolved at least 4 times in the past ∼30,000 years, including in another geographically distinct species, due to the high effective mutation rate which increases with titer. The higher titer viral type is associated with suppression of the host immune system and an increased transmission rate compared to the low viral titer type. Both types are maintained in all populations, likely due to an increased virulence in the high titer type creating a trade-off between effective transmission and virulence and resulting in nearly equal reproduction rates (R0) in both types. Together these results suggest that the reciprocal selective pressures caused by the co-evolution between host and virus has resulted in this recurrently evolving relationship.
Unique roles of ATAC and SAGA - KAT2A complexes in normal and malignant hematopoiesis
Authors: Arede Liliana , Foerner Elena , Wind Selinde , Kulkarni Rashmi , Domingues Ana Filipa , Kleinwaechter Svenja , Gupta Shikha , Scheer Elisabeth , Tora Laszlo , Pina Cristina
Published: May 2020

Epigenetic histone modifiers are key players in cell fate decisions. Significant research has focused on their enzymatic activity, but less is known about the contextual role of the complexes they integrate. We focus on KAT2A, a histone acetyltransferase we recently associated with leukemia stem cell maintenance, and which participates in ATAC and SAGA complexes. We show that ATAC is uniquely required for maintenance of normal and leukemia stem and progenitor cells, while SAGA more specifically contributes to cell identity. This dichotomy sets a paradigm for investigating epigenetic activities in their macromolecular context and informs epigenetic regulator targeting for translational purposes.