bluuebunny/crossref_metadata_2025 huggingface dataset:
The dynamic ontogenetic patterns of adaptive divergence and sexual dimorphism in Arctic charr
Authors: De la Cámara Marina , Ponsioen Lieke , Horta-Lacueva Quentin J.B. , Kapralova Kalina H
Published: January 2021

Arctic charr (Salvelinus alpinus) in lake Thingvallavatn (Iceland) is one of the most iconic examples of post-glacial adaptive divergence, resulting in four ecomorphs that diverge along the ecological benthic-limnetic axis (bottom lakeversusopen water feeders), and are distinct both phenotypically and genotypically. Here, we used geometric morphometrics tools on a common garden setup to determine the factors responsible for genetically based shape variation during the post-embryonic ontogeny of two morphs that represent the benthic-limnetic axis: the small benthic (SB) and the planktivorous (PL). This experiment uses pure crosses and F1 reciprocal hybrids between the two morphs, and includes the onset of sexual maturation, offering an excellent opportunity to explore the genetic component of adaptive divergence and the role of sexual dimorphism in this scenario. We found that growth is the main driver of shape variation across time and provided evidence of a genetically-controlled ontogenetic shift that gives rise to the limnetic morph. Additionally, our results indicate that the onset of sexual maturation triggers differences both in sex ontogenetic trajectories and in static shape variation at different time points, likely dissipating the canalisation for traits traditionally associated with benthic-limnetic adaptations.
Discovery of 10,828 new putative human immunoglobulin heavy chain IGHV variants
Authors: Martins Fabio R , de Melo Pontes Lucas Alves , de Oliveira Mendes Tiago Antônio , Felicori Liza F.
Published: January 2021

The correct identification of immunoglobulin alleles in genome sequences is a challenge. Nevertheless, it can assist in the study of several human diseases associated with the antibody repertoire and in the development of new therapies using antibody engineering techniques. The advent of next-generation sequencing of human genomes and antibody repertoires enabled the development of several tools for the mapping and identification of new immunoglobulin (Ig) alleles. Some of these tools use 1,000 Genomes (G1K) data for new Ig alleles discovery. However, genome data from G1K present low coverage and variant call problems. Here, a computational screen of immunoglobulin alleles was carried out in the Genome Aggregation Database (gnomAD), the largest high-quality catalogue of variation from 125,748 exomes and 15,708 human genomes.

A total of 10,909 putative IGHV alleles were identified, in which 10,828 of them are new and 2,024 appear at least in 6 different alleles from genomes/exomes. The IGHV2-70 was the IGHV gene segment with the largest number of variants described. The majority of the variants were found in the framework 3 and most of them are missense. Interestingly, a large number of variants were found to be population exclusive. A database integrated with a web platform was created (YGL-DB) to store and make accessible the likely new variants found.

This available data can help the scientific community to validate new IGHV variants as well as it can shed light on the importance of variants in disease development and immunization protocols.
Large-scale cellular-resolution imaging of neural activity in freely behaving mice
Authors: Leman D.P. , Chen I.A. , Bolding K.A. , Tai J. , Wilmerding L.K. , Gritton H.J. , Cohen Y. , Yen W.W. , Perkins L.N. , Liberti W.A. , Kilic K. , Han X. , Cruz-Martín A. , Gardner T.J. , Otchy T.M. , Davison I.G.
Published: January 2021

Miniaturized microscopes for head-mounted fluorescence imaging are powerful tools for visualizing neural activity during naturalistic behaviors, but the restricted field of view of first-generation ‘miniscopes’ limits the size of neural populations accessible for imaging. Here we describe a novel miniaturized mesoscope offering cellular-resolution imaging over areas spanning several millimeters in freely moving mice. This system enables comprehensive visualization of activity across entire brain regions or interactions across areas.
Raspberry pi: Assessments of emerging organic chemicals by the predictivein silicomethods
Authors: Arulanandam Charli Deepak , Prathiviraj R , Kaveriyappan Govindarajan Rasiravathanahalli
Published: January 2021

Phthalic acid esters (PAEs) and bisphenols are used as plasticizers worldwide. During plastic production, use, deposition, and recycling these compounds contaminate the environment and affect environmental health. In this study, we investigated the toxicity of plasticizers by usingin silicotools. None of the test compounds were found to be hERG blockers in multiclass predictions as evaluated by the Pred-hERG 4.1 tool. Among all tested compounds in Pred-Skin 2.0, only BBP, BCP, DBP, diethyl phthalate (DEP), DMP, DNHP, DNPP, DPP, DTDP, DUP, and ODP were non-skin sensitizers. Our results demonstrate thatin silicotools provide a reliable, fast, and economic way to explore the toxicological effects of EOCs.
Metabolism Control in 3D Printed Living Materials
Authors: Butelmann Tobias , Priks Hans , Parent Zoel , Johnston Trevor G. , Tamm Tarmo , Nelson Alshakim , Lahtvee Petri-Jaan , Kumar Rahul
Published: January 2021

The three-dimensional printing of cells offers an attractive opportunity to design and develop innovative biotechnological applications, such as the fabrication of biosensors or modular bioreactors. Living materials (LMs) are cross-linked polymeric hydrogel matrices containing cells, and recently, one of the most deployed LMs consists of F127-bis-urethane methacrylate (F127-BUM). The material properties of F127-BUM allow reproducible 3D printing and stability of LMs in physiological environments. These materials are permissible for small molecules like glucose and ethanol. However, no information is available for oxygen, which is essential— for example, towards the development of aerobic bioprocesses using microbial cell factories. To address this challenge, we investigated the role of oxygen as a terminal electron acceptor in the budding yeast’s respiratory chain and determined its permissibility in LMs. We quantified the ability of cell-retaining LMs to utilize oxygen and compared it with cells in suspension culture. We found that the cells’ ability to consume oxygen was heavily impaired inside LMs, indicating that the metabolism mostly relied on fermentation instead of respiration. To demonstrate an application of these 3D printed LMs, we evaluated a comparative brewing process. The analysis showed a significantly higher (3.7%) ethanol production using 3D printed LMs than traditional brewing, indicating an efficient control of the metabolism. Towards molecular and systems biology studies using LMs, we developed a highly reliable method to isolate cells from LMs for flow cytometry and further purified macromolecules (proteins, RNA, and DNA). Our results show the application of F127-BUM-based LMs for microaerobic processes and envision the development of diverse bioprocesses using versatile LMs in the future.
Single-cell sequencing of theDrosophilaembryonic heart and muscle cells during differentiation and maturation
Authors: Vogler Georg , Hum Bill , Tamayo Marco , Altman Yoav , Bodmer Rolf
Published: January 2021

The developingDrosophilaheart consists of cardioblasts that differentiate into different types of cardiomyocytes and pericardial cells. A large body of work has identified numerous genes and pathways involved in heart specification and differentiation, downstream of cardiac transcription factors, such as Tinman (NKX2-5) and Dorsocross1/2/3 (TBX5). The advent of single-cell RNA sequencing (scRNAseq) technology allowed us for the first time to describe the transcriptome of different cardiac cell types in theDrosophilamodel at high resolution. Here, we applied scRNAseq on sorted cells of late-stageDrosophilaembryos expressing a cardiac GFP reporter. We find distinct expression profiles of cardioblasts as they mature to cardiomyocytes, as well as discretely clustering pericardial cells, including a set expressing Tinman that potentially assist in heart morphogenesis. In addition, we describe other cell types that were sequenced as by-catch due to low but distinct extracardiac expression of the GFP reporter. Our studies on wildtype cardioblasts will be the foundation for investigating developmental profiles in mutant backgrounds and for generating gene regulatory networks at single-cell resolution during cardiogenesis.
PECAM-1 preserves cardiac function in pressure overload-induced biomechanical stress
Authors: McCormick Margaret E. , Rojas Mauricio , Reader John , Tzima Ellie
Published: January 2021

Background

Haemodynamic forces play a critical role in proper development of the heart, however much less is known about the mechanisms that regulate cardiac remodelling and function in response to haemodynamic stress in the adult. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a cell adhesion and signalling molecule that has important roles in regulation of junctional integrity, transendothelial migration and mechanotransduction in response to fluid shear stress. Our previous work identified a role for PECAM-1 in regulating baseline cardiac function via regulation of endothelial-cardiomyocyte communication.

Methods

This study investigates the role of PECAM-1 in cardiac remodelling in response to biomechanical stress due to pressure overload induced by transaortic constriction (TAC).

Results

Our data reveal that loss of PECAM-1 is associated with systolic dysfunction that is further accentuated following TAC. Adaptive increases in cardiomyocyte cross-sectional area, capillary density and hypertrophic gene expression were all affected with loss of PECAM-1. In control mice, maintained cardiac function was associated with activation of the c-Jun NH(2)-terminal kinase (JNK) pathway, whereas PECAM-1 deletion significantly decreased JNK activation after pressure overload. Our data suggest that in the absence of PECAM-1 signalling, inadequate remodelling of the heart under increased mechanical strain leads to further deterioration of cardiac function, characterized by reduced cardiomyocyte hypertrophy, capillary density and defects in the JNK signalling pathway.

Conclusions

Our study reveals a role for PECAM-1 in preservation of cardiac function in response to biomechanical stress induced by pressure overload.
Alternative futures for global biological invasions
Authors: Roura-Pascual Núria , Leung Brian , Rabitsch Wolfgang , Rutting Lucas , Vervoort Joost , Bacher Sven , Dullinger Stefan , Erb Karl-Heinz , Jeschke Jonathan M. , Katsanevakis Stelios , Kühn Ingolf , Lenzner Bernd , Liebhold Andrew M. , Obersteiner Michael , Pauchard Anibal , Peterson Garry D. , Roy Helen E. , Seebens Hanno , Winter Marten , Burgman Mark A. , Genovesi Piero , Hulme Philip E. , Keller Reuben P. , Latombe Guillaume , McGeoch Melodie A. , Ruiz Gregory M. , Scalera Riccardo , Springborn Michael R. , von Holle Betsy , Essl Franz
Published: January 2021

Scenario analysis has emerged as a key tool to analyze complex and uncertain future socio-ecological developments. However, current global scenarios (narratives of how the world may develop) have neglected biological invasions, a major threat to biodiversity and the economy. We used a novel participatory process to develop a diverse set of global biological invasion scenarios spanning a wide breadth of plausible global futures through 2050. We adapted the widely used “two axes” scenario analysis approach to develop four families of four scenarios each, resulting in 16 scenarios that were later clustered into four contrasting sets of futures. Our analysis highlighted that socio-economic developments and changes in sustainability policies and lifestyle have the potential to shape biological invasions, in addition to well-known ecological drivers, such as climate and human land use change. Our scenarios align fairly well with the recently developed shared socio-economic pathways, but the factors that drive differences in biological invasions are underrepresented there. Including these factors in global scenarios and models is essential to adequately consider biological invasions in global environmental assessments, and obtain a more integrative picture of future socio-ecological developments.
First evidence of nocardiosis in farmed red drum (Sciaenops ocellatus, Linnaeus) caused byNocardia seriolaein the Gulf of Mexico
Authors: del Rio-Rodriguez Rodolfo Enrique , Ramirez-Paredes Jose Gustavo , Soto-Rodriguez Sonia Araceli , Shapira Yechiam , del Jesus Huchin-Cortes Mariana , Ruiz-Hernandez Judith , Gomez-Solano Monica Isela , Haydon David
Published: January 2021

Between August and December 2013, the offshore cages of a commercial marine farm culturing red drumSciaenops ocellatusin Campeche Bay were affected by an outbreak of an ulcerative granulomatous disease, reaching 70% cumulative mortality. Thirty-one adults displaying open ulcers on the skin were submitted to our laboratory for diagnosis. Multiple white-yellowish nodules (0.1-0.5 cm in diameter) were present in all internal organs, where the kidney and the spleen were the most severely affected. Histopathological observations of these organs evinced typical granulomatous formations. Gram and Ziehl-Neelsen stains on tissue imprints, bacterial swabs and tissue sections revealed Gram-positive, acid-fast, branching beaded long rod filamentous bacteria. Tissue samples resulted positive for nocardiosis when aNocardiagenus specific nested PCR was used. Definite identification at the species level and taxonomic positioning of the fastidious pathogen was achieved through a specificNocardia seriolaePCR and by sequencing thegyrBgene of pure isolates. After application of antibiotics during fry production, a posterior follow-up monitoring (from 2014 to 2017) detected mild but recurrent outbreaks of the bacteria with no seasonality pattern. To the extent of our current knowledge, this is the first report of piscine nocardiosis (in a new host -red drum) in Mexico.
Exploring Parallel MPI Fault Tolerance Mechanisms for Phylogenetic Inference with RAxML-NG
Authors: Hübner Lukas , Kozlov Alexey M. , Hespe Demian , Sanders Peter , Stamatakis Alexandros
Published: January 2021

Phylogenetic trees are now routinely inferred on large scale HPC systems with thousands of cores as the parallel scalability of phylogenetic inference tools has improved over the past years to cope with the molecular data avalanche. Thus, the parallel fault tolerance of phylogenetic inference tools has become a relevant challenge. To this end, we explore parallel fault tolerance mechanisms and algorithms, the software modifications required, and the performance penalties induced via enabling parallel fault tolerance by example of RAxML-NG, the successor of the widely used RAxML tool for maximum likelihood based phylogenetic tree inference. We find that the slowdown induced by the necessary additional recovery mechanisms in RAxML-NG is on average 2%. The overall slowdown by using these recovery mechanisms in conjunction with a fault tolerant MPI implementation amounts to 8% on average for large empirical datasets. Via failure simulations, we show that RAxML-NG can successfully recover from multiple simultaneous failures, subsequent failures, failures during recovery, and failures during checkpointing. Recoveries are automatic and transparent to the user. The modified fault tolerant RAxML-NG code is available under GNU GPL athttps://github.com/lukashuebner/ft-raxml-ngContact: lukas.huebner@{kit.edu,h-its.org};,alexey.kozlov@h-its.org,hespe@kit.edu,sanders@kit.edu,alexandros.stamatakis@hits.orgSupplementary information: Supplementary data are available at bioRχiv.
Parallel adaptation in autopolyploidArabidopsis arenosais dominated by repeated recruitment of shared alleles
Authors: Konečná Veronika , Bray Sian , Vlček Jakub , Bohutínská Magdalena , Požárová Doubravka , Choudhury Rimjhim Roy , Bollmann-Giolai Anita , Flis Paulina , Salt David E , Parisod Christian , Yant Levi , Kolář Filip
Published: January 2021

Relative contributions of pre-existing vsde novogenomic variation to adaptation are poorly understood, especially in polyploid organisms, which maintain increased variation. We assess this in high resolution using autotetraploidArabidopsis arenosa, which repeatedly adapted to toxic serpentine soils that exhibit skewed elemental profiles. Leveraging a fivefold replicated serpentine invasion, we assess selection on SNPs and structural variants (TEs) in 78 resequenced individuals and discovered substantial parallelism in candidate genes involved in ion homeostasis. We further modelled parallel selection and inferred repeated sweeps on a shared pool of variants in nearly all these loci, supporting theoretical expectations. A single, striking exception is represented by TWO PORE CHANNEL 1, which exhibits convergent evolution from independentde novomutations at an identical, otherwise conserved site at the calcium channel selectivity gate. Taken together, this suggests that polyploid populations can rapidly adapt to environmental extremes, calling on both pre-existing variation and novel polymorphisms.
Multi-omic rejuvenation of human cells by maturation phase transient reprogramming
Authors: Gill Diljeet , Parry Aled , Santos Fátima , Hernando-Herraez Irene , Stubbs Thomas M. , Milagre Inês , Reik Wolf
Published: January 2021

Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first “maturation phase transient reprogramming” (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells reacquire their fibroblast identity following MPTR, possibly as a result of persisting epigenetic memory at enhancers. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent. The magnitude of rejuvenation instigated by MTPR is substantially greater than that achieved in previous transient reprogramming protocols. MPTR fibroblasts produced youthful levels of collagen proteins, suggesting functional rejuvenation. Overall, our work demonstrates that it is possible to separate rejuvenation from pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.

Highlights

We developed a novel method by which human fibroblasts are reprogrammed until the maturation phase of iPSCs and are then returned to fibroblast identity

DNA methylation memory in fibroblast enhancers may allow recovery of cell identity when fibroblast gene expression programmes are already extinct

Molecular measures of ageing including transcriptome and DNA methylation clocks and H3K9me3 levels reveal robust and substantial rejuvenation

Functional rejuvenation of fibroblasts by MPTR is suggested by reacquisition of youthful levels of collagen proteins
Chitinase 3-like-1 Stimulates PD-L1 and Other Immune Checkpoint Inhibitors
Authors: Ma Bing , Akosman Bedia , Kamle Suchitra , Lee Chang-Min , Koo Ja Seok , Lee Chun Geun , Elias Jack A.
Published: January 2021

PD-1 and its ligand PD-L1 are major mediators of tumor-induced immunosuppression. Chitinase 3-like-1 (Chi3l1) is induced in many cancers where it portends a poor prognosis and contributes to tumor metastasis. Here we demonstrate that Chi3l1 regulates the expression of PD-L1, PD-L2, PD-1 and LAG3 in melanoma lung metastasis. Chi3l1 stimulates macrophage PD-L1 expression and mediates optimal IFN-γ-stimulated PD-L1 expression via IL-13Rα2. We also demonstrate that RIG-like helicase innate immune activation suppresses Chi3l1, PD-L1, LAG3 and pulmonary metastasis. At least additive antitumor responses were seen in metastasis models treated simultaneously with individual antibodies against PD-1 and Chi3l1. At least additive cytotoxic T cell-induced tumor cell death was also seen in co-cultures of T and tumor cells treated with antibodies that target Chi3l1 and PD-1. Thus, Chi3l1 contributes to pulmonary metastasis by stimulating the PD1-PD-L1 axis and other checkpoint molecules. The simultaneous targeting of Chi3l1 and the PD-1-PD-L1 axis, represents a promising therapeutic strategy for pulmonary metastasis.
RIPK3 promoter hypermethylation in hepatocytes protects from bile acid induced inflammation and necroptosis
Authors: Hoff Jessica , Xiong Ling , Kammann Tobias , Neugebauer Sophie , Micheel Julia M. , Ghait Mohamed , Deshmukh Sachin , Gaßler Nikolaus , Bauer Michael , Press Adrian T.
Published: January 2021

Background & Aims

Necroptosis facilitates cell death in a controlled manner and is employed by many cell types following injury. It plays a major role in various liver diseases, albeit the cell type-specific regulation of necroptosis in the liver and especially hepatocytes has not yet been conceptualized.

Approaches & Results

Here, we demonstrate that DNA methylation suppresses RIPK3 expression in human hepatocytes and HepG2 cells. In diseases leading to cholestasis the RIPK3 expression is induced in mice and humans in a cell-type specific manner. Over-expression of RIPK3 in HepG2 cells leads immediately to RIPK3 activation by phosphorylation that is further modulated by different bile acids.

Conclusion

Bile acids mediated RIPK3 activation facilitates the secretion and expression of IL-8 via the JNK-pathway, suggesting hepatocytes suppress RIPK3 expression to protect themselves from bile acid induced necroptosis and inflammation but in chronical liver diseases associated with cholestasis induction of RIPK3 expression may be an early event signaling danger and repair through release of IL-8.

Graphical abstract
Graded Visual Consciousness During the Attentional Blink
Authors: Eiserbeck Anna , Enge Alexander , Rabovsky Milena , Rahman Rasha Abdel
Published: January 2021

One of the ongoing debates about visual consciousness is whether it can be considered as an all-or-none or a graded phenomenon. This may depend on the experimental paradigm and the task used to investigate this question. The present event-related potential study (N= 32) focuses on the attentional blink paradigm for which so far only little and mixed evidence is available. Detection of T2 face targets during the attentional blink was assessed via an objective accuracy measure (reporting the faces’ gender), subjective visibility on a perceptual awareness scale (PAS) as well as event-related potentials time-locked to T2 onset (components P1, N1, N2, and P3). The behavioral results indicate a graded rather than an all-or-none pattern of visual awareness. Corresponding graded differences in the N1, N2, and P3 components were observed for the comparison of visibility levels. These findings suggest that conscious perception during the attentional blink can occur in a graded fashion.
Refinement ofα-synuclein ensembles against SAXS data: Comparison of force fields and methods
Authors: Ahmed Mustapha Carab , Skaanning Line K. , Jussupow Alexander , Newcombe Estella A. , Kragelund Birthe B. , Camilloni Carlo , Langkilde Annette E. , Lindorff-Larsen Kresten
Published: January 2021

The inherent flexibility of intrinsically disordered proteins (IDPs) makes it difficult to interpret experimental data using structural models. On the other hand, molecular dynamics simulations of IDPs often suffer from force-field inaccuracies, and long simulations times or enhanced sampling methods are needed to obtain converged ensembles. Here, we apply metainference and Bayesian/Maximum Entropy reweighting approaches to integrate prior knowledge of the system with experimental data, while also dealing with various sources of errors and the inherent conformational heterogeneity of IDPs. We have measured new SAXS data on the proteinα-synuclein, and integrate this with simulations performed using different force fields. We find that if the force field gives rise to ensembles that are much more compact than what is implied by the SAXS data it is difficult to recover a reasonable ensemble. On the other hand, we show that when the simulated ensemble is reasonable, we can obtain an ensemble that is consistent with the SAXS data, but also with NMR diffusion and paramagnetic relaxation enhancement data.
Topological Sholl Descriptors For Neuronal Clustering and Classification
Authors: Khalil Reem , Kallel Sadok , Farhat Ahmad , Dłotko Paweł
Published: January 2021

Motivation

Given that neuronal morphology can widely vary among cell classes, brain regions, and animal species, accurate quantitative descriptions allowing classification of large sets of neurons is essential for their structural and functional characterization. However, robust and unbiased computational methods currently used to characterize groups of neurons are scarce.

Results

In this work, we introduce a novel and powerful technique to study neuronal morphologies. We develop mathematical descriptors that quantitatively characterize structural differences among neuronal cell types and thus allow for their accurate classification. Each Sholl descriptor that is assigned to a neuron is a function of a distance from the soma with values in real numbers or more general metric spaces. To illustrate the use of Sholl descriptors, six datasets were retrieved from the large public repositoryhttp://neuromorpho.org/comprising neuronal reconstructions from different species and brain regions. Sholl descriptors were subsequently computed, and standard clustering methods enhanced with detection and metric learning algorithms were then used to objectively cluster and classify each dataset. Importantly, our descriptors outperformed conventional techniques and thus provide a practical and effective approach to the classification of diverse neuronal cell types, with the potential for discovery of subclasses of neurons.
Selective metal extraction by biologically produced siderophores during bioleaching from low-grade primary and secondary mineral resources
Authors: Williamson Adam J. , Folens Karel , Matthijs Sandra , Cortez Yensy Paz , Varia Jeet , Laing Gijs Du , Boon Nico , Hennebel Tom
Published: January 2021

Siderophores are a class of biogenic macromolecules that have high affinities for metals in the environment, thus could be exploited for alternate sustainable metal recovery technologies. Here, we assess the role of siderophores in the extraction and complexation of metals from an iron oxide-rich metallurgical processing residue and a low-grade primary Ni ore. Evaluation of the biological siderophore bioproduction by three pseudomonads,P. fluorescens, P. azotoformansandP. putidaidentified thatP. putidacould generate the highest siderophore yield, which was characterized as a hydroxamate and catecholate mixed-type pyoverdine PyoPpC-3B. Key physiochemical parameters involved in raw siderophore mediated metal extraction were identified using a fractional factorial design of experiments (DOE) and subsequently employed in purified PyoPpC-3B leaching experiments. Further targeted experiments with hydroxamate and catecholate functional analogues of PyoPpC-3B confirmed their marked ability to competitively or selectively leach and chelate hard metal ions, including Al(OH)4-, Mn2+and Zn2+. Interestingly, complexation of Mn and Zn ions exceeded the natural affinity of pyoverdine for Fe3+, thus despite the low metal recoveries from the materials tested in this study, this work provides important new insights in siderophore-metal interactions.
Collective action or individual choice: Spontaneity and individuality contribute to decision-making inDrosophila
Authors: Steymans Isabelle , Pujol-Lereis Luciana M. , Brembs Björn , Gorostiza E. Axel
Published: January 2021

Our own unique character traits make our behavior consistent and define our individuality. Yet, this consistency does not entail that we behave repetitively like machines. Like humans, animals also combine personality traits with spontaneity to produce adaptive behavior: consistent, but not fully predictable. Here, we study an iconically rigid behavioral trait – insect phototaxis – that that nevertheless also contains both components of individuality and spontaneity. In a light/dark T-maze, approximately 70% of a group ofDrosophilafruit flies choose the bright arm of the T-Maze, while the remaining 30% walk into the dark. Taking the photopositive and the photonegative subgroups and re-testing them reveals the spontaneous component: a similar 70-30 distribution emerges in each of the two subgroups. Increasing the number of choices to ten choices, reveals the individuality component: flies with extremely negative first choices were more likely to show photonegative behavior in subsequent choices andvice versa. General behavioral traits, independent of light/dark preference, contributed to the development of this individuality. The interaction of individuality and spontaneity together explains why group averages, even for such seemingly stereotypical behaviors, are poor predictors of individual choices.
Ultrasound-mediated blood-brain barrier disruption improves anti-pyroglutamate3 Aβ antibody efficacy and enhances phagocyte infiltration into brain in aged Alzheimer’s disease-like mice
Authors: Shi Qiaoqiao , Sun Tao , Zhang Yongzhi , Power Chanikarn , Hoesch Camilla , Antonelli Shawna , Schroeder Maren K. , Caldarone Barbara J. , Taudte Nadine , Schenk Mathias , Hettmann Thore , Schilling Stephan , McDannold Nathan J. , Lemere Cynthia A.
Published: January 2021

Pyroglutamate-3 amyloid-β (pGlu3 Aβ) is an N-terminally modified, toxic form of amyloid-β that is present in cerebral amyloid plaques and vascular deposits. Using the Fc-competent murine anti-pGlu3 Aβ monoclonal antibody (mAb), 07/2a, we present here a nonpharmacological approach using focused ultrasound (FUS) with intravenous (i.v.) injection of microbubbles (MB) to facilitate i.v. delivery of the 07/2a mAb across the blood brain barrier (BBB) in order to improve Aβ removal and restore memory in aged APP/PS1 mice, an Alzheimer’s disease (AD)-like model of amyloidogenesis.

Compared to sham-treated controls, aged APP/PS1 mice treated with 07/2a immediately prior to FUS-mediated BBB disruption (mAb + FUS-BBBD combination treatment) showed significantly better spatial learning and memory in the Water T Maze. FUS-BBBD treatment alone improved contextual fear learning and memory in aged WT and APP/PS1 mice, respectively. APP/PS1 mice given the combination treatment had reduced Aβ42 and pGlu3 Aβ hippocampal plaque burden compared to PBS-treated APP/PS1 mice.

Hippocampal synaptic puncta density and synaptosomal synaptic protein levels were also higher in APP/PS1 mice treated with 07/2a just prior to BBB disruption. Increased Iba-1+microglia were observed in the hippocampi of AD mice treated with 07/2a with and without FUS-BBBD, and APP/PS1 mice that received hippocampal BBB disruption and 07/2a showed increased Ly6G+monocytes in hippocampal CA3. FUS-induced BBB disruption did not increase the incidence of microhemorrhage in mice with or without 07/2a mAb treatment.

Our findings suggest that FUS is useful tool that may enhance delivery of an anti-pGlu3 Aβ mAb for immunotherapy. FUS-mediated BBB disruption in combination with the 07/2a mAb also appears to facilitate monocyte infiltration in this AD model. Overall, these effects resulted in greater sparing of synapses and improved cognitive function without causing overt damage, suggesting the possibility of FUS as a noninvasive method to increase the therapeutic efficacy in AD patients.
Functional differences drive the selection of NRAS mutants in melanoma
Authors: Murphy Brandon M. , Weiss Tirzah J. , Holderbaum Andrea M. , Dhakal Aastha , Fort Marie , Bodnar Michael S. , Chen Min , Burd Craig J. , Coppola Vincenzo , Burd Christin E.
Published: January 2021

Distinct NRAS mutants are enriched in various tumor types. Here, we generated a suite of fully congenic, conditional,Nrasknock-in mouse models (LSL-Nras Q61R, -K, -L, -H, -P, -Q; G12DandG13D, -R) to test the hypothesis that melanocyte transformation requires functions specific to the NRAS mutants enriched in human melanoma (Q61R and Q61K). Consistent with the rarity of NRAS codon 12 and 13 mutants in human melanoma, spontaneous melanomas were rare or absent in mice expressing NRAS G12D, G13D or G13R. Mice expressing less common codon 61 alleles (Q61H, Q61P) also developed few or no tumors. NRAS Q61R, Q61K, or Q61L expression, by contrast, induced rapid melanoma onset with high penetrance. Cohorts of heterozygous mice containing oneLSL-Nras Q61Rand oneLSL-Nras Q61K, -L, -H, -P, or-Qallele were generated to assess potential interactions between NRAS mutants. The ability of eachNrasvariant to substitute for anNras Q61Rallele was consistent with its own ability to drive spontaneous melanoma formation. However,LSL-Nras Q61Q/Q61Rmice rarely developed tumors.In vitroexperiments in mouse embryonic fibroblasts (MEFs) highlighted activation of the MAPK pathway as a defining difference between tumorigenic and non-tumorigenic NRAS mutants. Enhanced MAPK activation was associated with the promotion of BRAF-BRAF and BRAF-CRAF dimers. These results support the development of cancer preventative strategies specific to the properties of the commonly observed RAS mutants in each tumor type.
LocalZProjectorandDeProj: A toolbox for local 2D projection and accurate morphometrics of large 3D microscopy images
Authors: Herbert Sébastien , Valon Léo , Mancini Laure , Dray Nicolas , Caldarelli Paolo , Gros Jérôme , Esposito Elric , Shorte Spencer L. , Bally-Cuif Laure , Levayer Romain , Aulner Nathalie , Tinevez Jean-Yves
Published: January 2021

Background

Quantitative imaging of epithelial tissues prompts for bioimage analysis tools that are widely applicable and accurate. In the case of imaging 3D tissues, a common pre-processing step consists in projecting the acquired 3D volume on a 2D plane mapping the tissue surface. Indeed, while segmenting the tissue cells is amenable on 2D projections, it is still very difficult and cumbersome in 3D. However, for many specimen and models used in Developmental and Cell Biology, the complex content of the image volume surrounding the epithelium in a tissue often reduces the visibility of the biological object in the projection, compromising its subsequent analysis. In addition, the projection may distort the geometry of the tissue and can lead to strong artifacts in the morphology measurement.

Results

Here we introduce a user-friendly toolbox built to robustly project epithelia on their 2D surface from 3D volumes, and to produce accurate morphology measurement corrected for the projection distortion, even for very curved tissues. Our toolbox is built upon two components.LocalZProjectoris a user-friendly and configurable Fiji plugin that generates 2D projections and height-maps from potentially large 3D stacks (larger than 40 GB per time-point) by only incorporating signal of the planes with local highest variance/mean intensity, despite a possibly complex image content.DeProjis a MATLAB tool that generates correct morphology measurements by combining the height-map output (such as the one offered byLocalZProjector) and the results of a cell segmentation on the 2D projection, hence effectively deprojecting the 2D segmentation in 3D. In this paper we demonstrate their effectiveness over a wide range of different biological samples. We then compare its performance and accuracy against similar existing tools.

Conclusions

We find thatLocalZProjectorperforms well even in situations where the volume to project also contains un-wanted signal in other layers. We show that it can process large images without a pre-processing step. We study the impact of geometrical distortions on morphological measurements induced by the projection. We measured very large distortions which are then corrected byDeProj, providing accurate outputs.
Stable thalamocortical learning between medial-dorsal thalamus and cortical attractor networks captures cognitive flexibility
Authors: Qiu Siwei
Published: January 2021

Primates and rodents are able to continually acquire, adapt, and transfer knowledge and skill, and lead to goal-directed behavior during their lifespan. For the case when context switches slowly, animals learn via slow processes. For the case when context switches rapidly, animals learn via fast processes. We build a biologically realistic model with modules similar to a distributed computing system. Specifically, we are emphasizing the role of thalamocortical learning on a slow time scale between the prefrontal cortex (PFC) and medial dorsal thalamus (MD). Previous work [1] has already shown experimental evidence supporting classification of cell ensembles in the medial dorsal thalamus, where each class encodes a different context. However, the mechanism by which such classification is learned is not clear. In this work, we show that such learning can be self-organizing in the manner of an automaton (a distributed computing system), via a combination of Hebbian learning and homeostatic synaptic scaling. We show that in the simple case of two contexts, the network with hierarchical structure can do context-based decision making and smooth switching between different contexts. Our learning rule creates synaptic competition [2] between the thalamic cells to create winner-take-all activity. Our theory shows that the capacity of such a learning process depends on the total number of task-related hidden variables, and such a capacity is limited by system size N. We also theoretically derived the effective functional connectivity as a function of an order parameter dependent on the thalamo-cortical coupling structure.

Significance Statement

Animals need to adapt to dynamically changing environments and make decisions based on changing contexts. Here we propose a combination of neural circuit structure with learning mechanisms to account for such behaviors. Specifically, we built a reservoir computing network improved by a Hebbian learning rule together with a synaptic scaling learning mechanism between the prefrontal cortex and the medial-dorsal (MD) thalamus. This model shows that MD thalamus is crucial in such context-based decision making. I also make use of dynamical mean field theory to predict the effective neural circuit. Furthermore, theoretical analysis provides a prediction that the capacity of such a network increases with the network size and the total number of tasks-related latent variables.
Ancient sedimentary DNA shows rapid post-glacial colonisation of Iceland followed by relatively stable vegetation until Landnám
Authors: Alsos Inger Greve , Lammers Youri , Kjellman Sofia E. , Føreid Merkel Marie Kristine , Bender Emma M. , Rouillard Alexandra , Erlendsson Egill , Guðmundsdóttir Esther Ruth , Benediktsson Ívar Örn , Farnsworth Wesley R. , Brynjólfsson Skafti , Gísladóttir Guðrún , Eddudóttir Sigrún Dögg , Schomacker Anders
Published: January 2021

Understanding patterns of colonisation is important for explaining both the distribution of single species and anticipating how ecosystems may respond to global warming. Insular flora may be especially vulnerable because oceans represent severe dispersal barriers. Here we analyse two lake sediment cores from Iceland for ancient sedimentary DNA to infer patterns of colonisation and Holocene vegetation development. Our cores from lakes Torfdalsvatn and Nykurvatn span the lastc. 12,000 cal. yr BP andc. 8600 cal. yr BP, respectively. With near-centennial resolution, we identified a total of 191 plant taxa, with 152 taxa identified in the sedimentary record of Torfdalsvatn and 172 plant taxa in the sedimentary record of Nykurvatn. The terrestrial vegetation at Torfdalsvatn was first dominated by bryophytes, arctic herbs such asSaxifragaspp. and grasses. Around 10,100 cal. yr BP, a massive immigration of new taxa was observed, and shrubs and dwarf shrubs became common whereas aquatic macrophytes became dominant. At Nykurvatn, all dominant taxa occurred already in the earliest samples; shrubs and dwarf shrubs were more abundant at this site than at Torfdalsvatn. There was an overall steep increase both in the local and regional species pool until 8000 cal. yr BP, by which time ¾ of all taxa identified had arrived. In the period 4500-1000 cal. yr BP, a few new taxa of bryophytes, graminoids and forbs are identified. The last millennium, after human settlement of the island (Landnám), is characterised by a sudden disappearance ofJuniperus communis, but also reappearance of some high arctic forbs and dwarf shrubs. Notable immigration during the Holocene coincides with periods of dense sea-ice cover, and we hypothesise that this may have acted as a dispersal vector. Thus, although ongoing climate change might provide a suitable habitat in Iceland for a large range of species only found in the neighbouring regions today, the reduction of sea ice may in fact limit the natural colonisation of new plant species.
Metacommunities, fitness and gradual evolution
Authors: Priklopil Tadeas , Lehmann Laurent
Published: January 2021

We analyze the evolution of a multidimensional quantitative trait in a class structured focal species interacting with other species in a wider metacommunity. The evolutionary dynamics in the focal species as well as the ecological dynamics of the whole metacommunity is described as a continuous time process with birth, physiological development, dispersal, and death given as rates that can depend on the state of the whole metacommunity. This can accommodate complex local community and global metacommunity environmental feedbacks owing to inter- and intra-specific interactions, as well as local environmental stochastic fluctuations. For the focal species, we derive a fitness measure for a mutant allele affecting class-specific trait expression. Using classical results from geometric singular perturbation theory, we provide a detailed proof that if the effect of the mutation on phenotypic expression is small (“weak selection”), the large system of dynamical equations needed to describe selection on the mutant allele in the metacommunity can be reduced to a single ordinary differential equation on the arithmetic mean mutant allele frequency that is of constant sign. This invariance on allele frequency entails the mutant either dies out or will out-compete the ancestral resident (or wild) type. Moreover, the directional selection coefficient driving arithmetic mean allele frequency can be expressed as an inclusive fitness effect calculated from the resident metacommunity alone, and depends, as expected, on individual fitness differentials, relatedness, and reproductive values. This formalizes the Darwinian process of gradual evolution driven by random mutation and natural selection in spatially and physiologically class structured metacommunities.
Genotypic variation in soil penetration by maize roots is negatively related to ethylene-induced thickening
Authors: Vanhees Dorien J. , Schneider Hannah M. , Loades Kenneth W. , Bengough A. Glyn , Bennett Malcolm J. , Pandey Bipin K. , Brown Kathleen M. , Mooney Sacha J. , Lynch Jonathan P.
Published: January 2021

Radial expansion is a classic response of roots to mechanical impedance that has generally been assumed to aid penetration. We analysed the response of maize nodal roots to impedance to test the hypothesis that radial expansion is not related to the ability of roots to cross a compacted soil layer. Genotypes varied in their ability to cross the compacted layer, and those with a steeper approach to the compacted layer or less radial expansion in the compacted layer were more likely to cross the layer and achieve greater depth. Root radial expansion was due to cortical cell size expansion, while cortical cell file number remained constant. Genotypes and nodal root classes that exhibited radial expansion upon encountering the compacted soil layer also thickened in response to exogenous ethylene in hydroponic culture, i.e. radial expansion in response to ethylene was correlated with the thickening response to impedance in soil. We propose that ethylene insensitive roots, i.e. those that do not thicken and are able to overcome impedance, have a competitive advantage under mechanically impeded conditions as they can maintain their elongation rates. We suggest that prolonged exposure to ethylene could function as a stop signal for axial root growth.
In vitromaturation ofToxoplasma gondiibradyzoites in human myotubes and their metabolomic characterization
Authors: Christiansen Céline , Maus Deborah , Hoppenz Ellen , Murillo-León Mateo , Hoffmann Tobias , Scholz Jana , Melerowicz Florian , Steinfeldt Tobias , Seeber Frank , Blume Martin
Published: January 2021

The apicomplexan parasiteToxoplasma gondiiforms bradyzoite-containing tissue cysts that cause chronic and drug-tolerant infections. However, currentin vitromodels do not allow long-term culture of these cysts to maturity. Here, we developed a human myotube-basedin vitroculture model of functionally mature tissue cysts that are orally infectious to mice and tolerate exposure to a range of antibiotics and temperature stresses. Metabolomic characterization of purified cysts reveals global changes that comprise increased levels of amino acids and decreased abundance of nucleobase- and tricarboxylic acid cycle-associated metabolites. In contrast to fast replicating tachyzoite forms ofT. gondiithese tissue cysts tolerate exposure to the aconitase inhibitor sodium fluoroacetate. Direct access to persistent stages ofT. gondiiunder defined cell culture conditions will be essential for the dissection of functionally important host-parasite interactions and drug evasion mechanisms. It will also facilitate the identification of new strategies for therapeutic intervention.
Multi-metabolomics using imaging mass spectrometry and liquid chromatography-tandem mass spectrometry for spatially characterizing monoterpene indole alkaloids secreted from roots
Authors: Nakabayashi Ryo , Takeda-Kamiya Noriko , Yamada Yutaka , Mori Tetsuya , Uzaki Mai , Nirasawa Takashi , Toyooka Kiminori , Saito Kazuki
Published: January 2021

Plants release specialized (secondary) metabolites from their roots to communicate with other organisms, including soil microorganisms. The spatial behavior of such metabolites around these roots can help us understand roles for the communication; however, currently they are unclear because soil-based studies are complex. Here, we established a multi-metabolomics approach using imaging mass spectrometry (IMS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to spatially assign metabolites under laboratory conditions using agar. In a case study usingCatharanthus roseus, we showed that 58 nitrogen (N)-containing metabolites are released from the roots into the agar. For the metabolite assignment, we used15N-labeled and nonlabeled LC-MS/MS data, previously reported. Four metabolite ions were identified using authentic standard compounds as derived from monoterpene indole alkaloids (MIAs) such as ajmalicine, catharanthine, serpentine, and yohimbine. An alkaloid network analysis using dot products and spinglass methods characterized five clusters to which the 58 ions belong. The analysis clustered ions from the indolic skeleton-type MIAs to a cluster, suggesting that other communities may represent distinct metabolite groups. For future chemical assignments of the serpentine community, key fragmentation patterns were characterized using the15N-labeled and nonlabeled MS/MS spectra.