bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding implicit sensorimotor adaptation as a process of proprioceptive re-alignment
Authors: Tsay Jonathan S. , Kim Hyosub E. , Haith Adrian M. , Ivry Richard B.
Published: December 2021

Multiple learning processes contribute to successful goal-directed actions in the face of changing physiological states, biomechanical constraints, and environmental contexts. Amongst these processes, implicit sensorimotor adaptation is of primary importance, ensuring that movements remain well-calibrated and accurate. A large body of work on reaching movements has emphasized how adaptation centers on an iterative process designed to minimize visual errors. The role of proprioception has been largely neglected, thought to play a passive role in which proprioception is affected by the visual error but does not directly contribute to adaptation. Here we present an alternative to this visuo-centric framework, arguing that that implicit adaptation can be understood as minimizing a proprioceptive error, the distance between the perceived hand position and its intended goal. We use this proprioceptive re-alignment model (PReMo) to re-examine many phenomena that have previously been interpreted in terms of learning from visual errors, as well as offer novel accounts for unexplained phenomena. We discuss potential challenges for this new perspective on implicit adaptation and outline a set of predictions for future experimentation.
Ciliary neurotrophic factor-mediated neuroprotection involves enhanced glycolysis and anabolism in degenerating mouse retinas
Authors: Do Rhee Kun , Wang Yanjie , ten Hoeve Johanna , Stiles Linsey , Nguyen Thao Thi Thu , Zhang Xiangmei , Vergnes Laurent , Reue Karen , Shirihai Orian , Bok Dean , Yang Xian-Jie
Published: December 2021

Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective cytokine in multiple models of retinal degeneration. To understand mechanisms underlying its broad neuroprotective effects, we have investigated the influence of CNTF on metabolism in a mouse model of photoreceptor degeneration. CNTF treatment improves the morphology of photoreceptor mitochondria, but also leads to reduced oxygen consumption and suppressed respiratory chain activities. Molecular analyses show elevated glycolytic pathway gene transcripts and active enzymes. Metabolomics analyses detect significantly higher levels of ATP and the energy currency phosphocreatine, elevated glycolytic pathway metabolites, increased TCA cycle metabolites, lipid biosynthetic pathway intermediates, nucleotides, and amino acids. Moreover, CNTF treatment restores the key antioxidant glutathione to the wild type level. Therefore, CNTF significantly impacts the metabolic status of degenerating retinas by promoting aerobic glycolysis and augmenting anabolic activities. These findings reveal cellular mechanisms underlying enhanced neuronal viability and suggest potential therapies for treating retinal degeneration.
Local activation of focal adhesion kinase orchestrates the positioning of presynaptic scaffold proteins and Ca2+ channel function to control glucose dependent insulin secretion
Authors: Hallahan Nicole , Deng Kylie , Jevon Dillon , Kumar Krish , Tong Jason , Gan Wan Jun , Tran Clara , Bilek Marcela , Thorn Peter
Published: December 2021

A developing understanding suggests that spatial compartmentalisation of components the glucose stimulus-secretion pathway in pancreatic β cells are critical in controlling insulin secretion. To investigate the mechanisms, we have developed live-cell sub-cellular imaging methods using the organotypic pancreatic slice. We demonstrate that the organotypic pancreatic slice, when compared with isolated islets, preserves intact β cell structure, and enhances glucose dependent Ca2+ responses and insulin secretion. Using the slice technique, we have discovered the essential role of local activation of integrins and the downstream component, focal adhesion kinase, in regulating β cells. Integrins and focal adhesion kinase are exclusively activated at the β cell capillary interface and using in situ and in vitro models we show their activation both positions presynaptic scaffold proteins, like ELKS and liprin, and regulates glucose dependent Ca2+ responses and insulin secretion. We conclude that focal adhesion kinase orchestrates the final steps of glucose dependent insulin secretion within the restricted domain where β cells contact the islet capillaries.
Soil collected in the Great Smoky Mountains National Park yielded a novelListeriaspecies,L. swaminathanii, effectively expanding thesensu strictoclade to ten species
Authors: Carlin Catharine R. , Liao Jingqiu , Hudson Lauren K. , Peters Tracey L. , Denes Thomas G. , Orsi Renato , Guo Xiaodong , Wiedmann Martin
Published: December 2021

Soil samples collected in the Great Smoky Mountains National Park yielded aListeriaisolate that could not be classified to the species level. Whole-genome sequence-based average nucleotide identity BLAST andin silicoDNA-DNA Hybridization analyses confirmed this isolate to be a novelListeria sensu strictospecies with the highest similarity toL. marthii(ANI=93.9%, isDDH=55.9%). Additional whole-genome-based analysis using the Genome Taxonomy Database Toolkit, an automated program for classifying bacterial genomes, further supported delineation as a novelListeria sensu strictospecies, as this tool failed to assign a species identification but identifiedL. marthiias the closest match. Phenotypic and genotypic characterization results indicate that this species is nonpathogenic. Specifically, the novelListeriaspecies described here is phenotypically (i) non-hemolytic and (ii) negative for phosphatidylinositol-specific phospholipase C activity; the draft genome lacks all virulence genes found in theListeriapathogenicity island 1 (LIPI-1), as well as the internalin genesinlAandinlB. While the type strain for the new species is phenotypically catalase-negative (an unusual characteristic forListeria sensu strictospecies), its genome contained an apparently intact catalase gene (kat); hence assessment of this phenotype with future isolates will be important. Rapid species identification systems (ListeriaAPI, VITEK 2, VITEK MS) misidentified this novel species as eitherL. monocytogenes, L. innocua, orL. marthii. We propose the nameL. swaminathanii, and the type strain is FSL L7-0020T(=ATCC TSD-239T).

IMPORTANCE

L. swaminathaniiis a novelsensu strictospecies that originated from a US National Park, and its place of origin is ultimately preventing this species from achieving valid status. The US National Park Service restricts strain accessibility and open access is currently a prerequisite for species validation. Essentially the only criteria that was not met forL. swaminathaniivalidation is accessibility of the type strain, therefore nomenclature status should not negate the significance of this discovery. As a novelsensu strictospecies,L. swaminathaniiexpands the group of species whose presence is associated with an increased risk of anL. monocytogenescontamination, and therefore could play an important role in public health. While developers ofListeriaspp. detection methods historically only included validly publish species in their validation studies,L. swaminathaniiis unequivocally asensu strictospecies and should be included as well.
Novel regimens of bedaquiline-pyrazinamide combined with moxifloxacin, rifabutin, delamanid and/or OPC-167832 in murine tuberculosis models
Authors: Tasneen Rokeya , Garcia Andrew , Converse Paul J. , Zimmerman Matthew D. , Dartois Veronique , Kurbatova Ekaterina , Vernon Andrew A. , Carr Wendy , Stout Jason E. , Dooley Kelly E. , Nuermberger Eric L.
Published: December 2021

A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin and isoniazid (PZMH) to be non-inferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.e., BZM) significantly reduced both lung CFU counts after 1 month and the proportion of mice relapsing within 3 months after completing 1.5 months of treatment. Addition of rifabutin to BZM (BZMRb) further increased the sterilizing activity. In the C3HeB/FeJ mouse model characterized by caseating lung lesions, treatment with BZMRb resulted in significantly fewer relapses than PZMH after 2 months of treatment. A regimen combining the new DprE1 inhibitor OPC-167832 and delamanid (BZOD) also had superior bactericidal and sterilizing activity compared to PZM in BALB/c mice and was similar in efficacy to PZMH in C3HeB/FeJ mice. Thus, BZM represents a promising backbone for treatment-shortening regimens. Given the prohibitive drug-drug interactions between bedaquiline and rifampin or rifapentine, the BZMRb regimen represents the best opportunity to combine, in one regimen, the treatment-shortening potential of the rifamycin class with that of BZM and deserves high priority for evaluation in clinical trials. Other 4-drug BZM-based regimens and BZOD represent promising opportunities for extending the spectrum of treatment-shortening regimens to rifamycin- and fluoroquinolone-resistant tuberculosis.
NK cells acquire CCR5 and CXCR4 by trogocytosis in people living with HIV-1
Authors: Vo Dang-Nghiem , Leventoux Nicolas , Campos-Mora Mauricio , Gimenez Sandrine , Corbeau Pierre , Villalba Martin
Published: December 2021

NK cells play a major role in the antiviral immune response, including against HIV-1. HIV patients have impaired NK cell activity with decrease in CD56dim NK cells and increase in CD56−CD16+ subset and recently it has been proposed that a population of CD56+NKG2C+KIR+CD57+ cells represents antiviral memory NK cells. Antiretroviral therapy (ART) partly restores the functional activity of this lymphocyte lineage. NK cells when interacting with their targets can gain antigens from them by the process of trogocytosis. Here we show that NK cells can obtain CCR5 and CXCR4, but barely CD4, from T cell lines by trogocytosis in vitro. By UMAP (Uniform Manifold Approximation and Projection), we show that aviremic HIV patients have unique NK cell clusters that encompass for cells expressing CCR5, NKG2C and KIRs, but lack CD57 expression. Viremic patients have a larger proportion of CXCR4+ and CCR5+ NK cells than healthy donors (HD) and this is largely increased in CD107+ cells, suggesting a link between degranulation and trogocytosis. In agreement, UMAP identified a specific NK cell cluster in viremic HIV patients, which contains most of the CD107a+, CCR5+ and CXCR4+ cells. However, this cluster lacks NKG2C expression. Therefore, NK cells can gain CCR5 and CXCR4 by trogocytosis, which depends on degranulation.

Author Summary

NK cells play a major role in the antiviral immune response, including against HIV-1. HIV-1 infection largely impacts NK cell lineage. However, identification of the NK cells fighting the virus and eliminating infected cells has remained elusive. By using FACs analysis and analyzing T cell markers, we identify specific NK cell subsets that have gained T cell antigen markers by trogocytosis. We show a strong association of degranulation and trogocytosis ex vivo suggesting that NK cells are eliminating or trying to eliminate HIV-1 infected cells.

Moreover, we show that NK cells can obtain the HIV-1 coreceptors CCR5 and CXCR4, but barely CD4, from T cells. Therefore, by uncovering that NK cells gain CCR5 and CXCR4 by trogocytosis we show that NK cells are actively fighting against HIV-1 infection in viremic and aviremic patients. This should help to identify why certain patients better control the virus, to develop new anti-HIV-1, NK cell-based, immunotherapies and to understand if NK cells can be a new HIV-1 reservoir.
Phenotyping Polarization Dynamics Of Immune Cells Using A Lipid Droplet - Cell Pairing Microfluidic Platform
Authors: Pinon Léa , Ruyssen Nicolas , Pineau Judith , Mesdjian Olivier , Cuvelier Damien , Chipont Anna , Allena Rachele , Guerin Coralie L. , Asnacios Sophie , Asnacios Atef , Pierobon Paolo , Fattaccioli Jacques
Published: December 2021

The immune synapse is the tight contact zone between a lymphocyte and a cell presenting its cognate antigen. This structure serves as a signaling platform and entails a polarization of intra-cellular components, necessary to the immunological function of the cell. While the surface properties of the presenting cell are known to control the formation of the synapse, their impact on polarization has not yet been studied.

Using functional lipid droplets as tunable artificial presenting cells combined with a microfluidic pairing device, we simultaneously observe synchronized synapses and dynamically quantify polarization patterns of individual B cells. By assessing how ligand concentration, surface fluidity and substrate rigidity impact lysosome polarization, we show that its onset and kinetics depend on the local antigen concentration at the synapse and on substrate rigidity. Our experimental system enables a fine phenotyping of monoclonal cell populations based on their synaptic readout.
A guide to trajectory inference and RNA velocity
Authors: Weiler Philipp , Van den Berge Koen , Street Kelly , Tiberi Simone
Published: December 2021

Technological developments have led to an explosion of high-throughput single cell data, which are revealing unprecedented perspectives on cell identity. Recently, significant attention has focused on investigating, from single-cell RNA-sequencing (scRNA-seq) data, cellular dynamic processes, such as cell differentiation, cell cycle and cell (de)activation. Trajectory inference methods estimate a trajectory, a collection of differentiation paths of a dynamic system, by ordering cells along the paths of such a dynamic process. While trajectory inference tools typically work with gene expression levels, common scRNA-seq protocols allow the identification and quantification of unspliced pre-mRNAs and mature spliced mRNAs, for each gene. By exploiting the abundance of unspliced and spliced mRNA, one can infer the RNA velocity of individual cells, i.e., the time derivative of the gene expression state of cells. Whereas traditional trajectory inference methods reconstruct cellular dynamics given a population of cells of varying maturity, RNA velocity relies on a dynamical model describing splicing dynamics. Here, we initially discuss conceptual and theoretical aspects of both approaches, then illustrate how they can be combined together, and finally present an example use-case on real data.
The dual role of the RETINOBLASTOMA-RELATED protein in the DNA damage response is spatio-temporally coordinated by the interaction with LXCXE-containing proteins
Authors: Zaragoza Jorge Zamora , Klap Katinka , Heidstra Renze , Zhou Wenkun , Scheres Ben
Published: December 2021

Living organisms face threats to genome integrity caused by environmental challenges or metabolic errors in proliferating cells. To avoid the spread of mutations, cell division is temporarily arrested while repair mechanisms deal with DNA lesions. Afterwards, cells either resume division or respond to unsuccessful repair by withdrawing from the cell cycle and undergoing cell differentiation or cell death. How the success rate of DNA repair connects to the execution of cell death remains incompletely known, particularly in plants. Here we provide evidence that the Arabidopsis thaliana RETINOBLASTOMA-RELATED1 (RBR) protein, shown to play structural and transcriptional functions in the DNA damage response (DDR), coordinates these processes in time by successive interactions through its B-pocket sub-domain. Upon DNA damage induction, RBR forms nuclear foci; but the N849F substitution in the B-pocket, which specifically disrupts binding to LXCXE motif-containing proteins, abolishes RBR focus formation and leads to growth arrest. After RBR focus formation, the stress-responsive gene NAC044 arrests cell division. As RBR is released from nuclear foci, it can be bound by the conserved LXCXE motif in NAC044. RBR-mediated cell survival is inhibited by the interaction with NAC044. Disruption of NAC044-RBR interaction impairs the cell death response but is less important for NAC044 mediated growth arrest. Noteworthy, unlike many RBR interactors, NAC044 binds to RBR independent of RBR phosphorylation. Our findings indicate that the availability of the RBR B-pocket to interact with LXCXE-containing proteins couples RBR DNA repair functions and RBR transcriptional functions of in the cell death program.
Chronic Alcohol Dysregulates Glutamatergic Function in the Basolateral Amygdala in a Projection- and Sex-Specific Manner
Authors: Price Michaela E. , McCool Brian A.
Published: December 2021

Chronic intermittent ethanol (CIE) produces alcohol dependence, facilitates anxiety-like behavior, and increases post-CIE alcohol intake. The basolateral amygdala (BLA) is one of several brain regions that regulates anxiety-like behavior and alcohol intake through downstream projections. The BLA receives information from two distinct input pathways. Afferents from medial structures like the thalamus and prefrontal cortex enter the BLA through thestria terminaliswhereas lateral cortical structures like the anterior insula cortex enter the BLA through the external capsule. CIE induces input- and sex-specific adaptations to glutamatergic function in the BLA. Previous studies sampled neurons throughout the BLA, but did not distinguish between projection-specific populations. The current study investigated BLA neurons that project to the NAC (BLA-NAC neurons) or the BNST (BLA-BNST neurons) as representative ‘reward’ and ‘aversion’ BLA neurons, and showed that CIE alters glutamatergic function and excitability in a projection- and sex-specific manner. CIE increases glutamate release fromstria terminalisinputs only onto BLA-BNST neurons. At external capsule synapses, CIE increases postsynaptic glutamatergic function in male BLA-NAC neurons and female BLA-BNST neurons. Subsequent experiments demonstrated that CIE enhanced the excitability of male BLA-NAC neurons and BLA-BNST neurons in both sexes when glutamatergic but not GABAergic function was intact. Thus, CIE-mediated increased glutamatergic function facilitates hyperexcitability in male BLA-NAC neurons and BLA-BNST neurons of both sexes.
Function-guided protein design by deep manifold sampling
Authors: Gligorijević Vladimir , Berenberg Daniel , Ra Stephen , Watkins Andrew , Kelow Simon , Cho Kyunghyun , Bonneau Richard
Published: December 2021

Protein design is challenging because it requires searching through a vast combinatorial space that is only sparsely functional. Self-supervised learning approaches offer the potential to navigate through this space more effectively and thereby accelerate protein engineering. We introduce a sequence denoising autoencoder (DAE) that learns the manifold of protein sequences from a large amount of potentially unlabelled proteins. This DAE is combined with a function predictor that guides sampling towards sequences with higher levels of desired functions. We train the sequence DAE on more than 20M unlabeled protein sequences spanning many evolutionarily diverse protein families and train the function predictor on approximately 0.5M sequences with known function labels. At test time, we sample from the model by iteratively denoising a sequence while exploiting the gradients from the function predictor. We present a few preliminary case studies of protein design that demonstrate the effectiveness of this proposed approach, which we refer to as “deep manifold sampling”, including metal binding site addition, function-preserving diversification, and global fold change.
Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis
Authors: Sala Davide , Ornaghi Francesca , Morena Francesco , Argentati Chiara , Valsecchi Manuela , Alberizzi Valeria , Di Guardo Roberta , Bolino Alessandra , Aureli Massimo , Martino Sabata , Gritti Angela
Published: December 2021

The GM2 gangliosidoses Tay-Sachs disease and Sandhoff disease (SD) are respectively caused by mutations in the HEXA and HEXB genes encoding the α and β subunits of β-N-acetylhexosaminidase (Hex). The consequential accumulation of ganglioside in the brain leads to severe and progressive neurological impairment. There are currently no approved therapies to counteract or reverse the effects of GM2 gangliosidosis. Adeno-associated vector (AAV)-based investigational gene therapy (GT) products have raised expectations but come with safety and efficacy issues that need to be addressed. Thus, there is an urgent need to develop novel therapies targeting the CNS and other affected tissues that are appropriately timed to ensure pervasive metabolic correction and counteract disease progression. In this report, we show that the sequential administration of lentiviral vector (LV)-mediated intracerebral (IC) GT and bone marrow transplantation (BMT) in pre-symptomatic SD mice provide a timely and long-lasting source of the Hex enzyme in the central and peripheral nervous systems and peripheral tissues, leading to global rescue of the disease phenotype. Combined therapy showed a clear therapeutic advantage compared to individual treatments in terms of lifespan extension and normalization of the neuroinflammatory and neurodegenerative phenotypes of the SD mice. These benefits correlated with a time-dependent increase in Hex activity and a remarkable reduction in GM2 storage in the brain tissues that single treatments failed to achieve. Our results highlight the complementary and synergic mode of action of LV-mediated IC GT and BMT, clarify the relative contribution of treatments to the therapeutic outcome, and inform on the realistic threshold of enzymatic activity that is required to achieve a significant therapeutic benefit, with important implications for the monitoring and interpretation of ongoing experimental therapies, and for the design of more effective treatment strategies for GM2 gangliosidosis.
ATP:Mg2+shapes condensate properties of rRNA-NPM1in vitronucleolus model and its partitioning of ribosomes
Authors: Yewdall N. Amy , André Alain A. M. , van Haren Merlijn H. I. , Nelissen Frank H.T. , Jonker Aafke , Spruijt Evan
Published: December 2021

Nucleoli have viscoelastic gel-like condensate dynamics that are not well representedin vitro. Nucleoli models, such as those formed by nucleophosmin 1 (NPM1) and ribosomal RNA (rRNA), exhibit condensate dynamics orders of magnitude faster thanin vivonucleoli. Here we show that an interplay between magnesium ions (Mg2+) and ATP governs rRNA dynamics, and this ultimately shapes the physical state of these condensates. Using quantitative fluorescence microscopy, we demonstrate that increased RNA compaction occurs in the condensates at high Mg2+concentrations, contributing to the slowed RNA dynamics. At Mg2+concentrations above 7 mM, rRNA is fully arrested and the condensates are gels. Below the critical gel point, NPM1-rRNA droplets age in a temperature-dependent manner, suggesting that condensates are viscoelastic materials, undergoing maturation driven by weak multivalent interactions. ATP addition reverses the dynamic arrest of rRNA, resulting in liquefaction of these gel-like structures. Surprisingly, ATP and Mg2+both act to increase partitioning of NPM1-proteins as well as rRNA, which influences the partitioning of small client molecules. By contrast, larger ribosomes form a halo around NPM1-rRNA coacervates when Mg2+concentrations are higher than ATP concentrations. Within cells, ATP levels fluctuate due to biomolecular reactions, and we demonstrate that a dissipative enzymatic reaction can control the biophysical properties ofin vitrocondensates through depletion of ATP. This enzymatic ATP depletion also reverses the formation of the ribosome halos. Our results illustrate how cells, by changing local ATP concentrations, may regulate the state and client partitioning of RNA-containing condensates such as the nucleolus.

Significance Statement

There is a significant discrepancy between the dynamics ofin vitronucleolus models andin vivonucleoli – with the latter more gel-like.

The interplay between Mg2+ions, ATP and the nucleolus components – specifically RNA – governs the dynamics, and ultimately the physical state, of nucleolus-like condensates.

We show that the nucleolus are dynamically adapting condensates, responding to local ATP concentrations through Mg2+-induced compaction of the RNA, and reversible relaxation when ATP binds Mg2+again. Other condensates containing RNA probably respond in similar ways to Mg2+and ATP.
The microRNA miR-132 is a key regulator of lymphatic vascular remodelling
Authors: Arcucci Valeria , Ishaq Musarat , Roufail Sally , Dredge B. Kate , Bert Andrew G. , Hackett-Jones Emily , Liu Ruofei , Pillman Katherine A. , Fox Stephen B. , Stacker Steven A. , Goodall Gregory J. , Achen Marc G.
Published: December 2021

Lymphangiogenesis (growth of new lymphatic vessels), and lymphatic remodelling more broadly, are important for disease progression in cancer, lymphedema and the pulmonary disease lymphangioleiomyomatosis. Multiple molecular pathways which signal for aspects of lymphangiogenesis are known but little is understood about their co-ordinate regulation in lymphatic endothelial cells (LECs). Small RNA molecules co-ordinately regulate complex biological processes, but knowledge about their involvement in lymphangiogenesis is limited. Here we used high-throughput small RNA sequencing of LECs to identify microRNAs (miRs) regulating lymphatic remodelling driven by the lymphangiogenic growth factors VEGF-C and VEGF-D. We identified miR-132 as up-regulated by both growth factors, and demonstrated that inhibiting miR-132 in LECs in vitro blocked cell proliferation and tube formation, key steps in lymphangiogenesis. We showed that miR-132 is expressed in human LECs in vivo in the lymphatics of human breast tumours expressing VEGF-D. Importantly, we demonstrated that inhibiting miR-132 in vivo blocked many aspects of lymphangiogenesis in mice. Finally, we identified mRNAs regulated by miR-132 in LECs, by sequencing after RNA-protein cross-linking and Argonaute immunoprecipitation, which demonstrated how miR-132 co-ordinately regulates signalling pathways in lymphangiogenesis. This study shows miR-132 is a critical regulator of lymphangiogenesis and a potential target for therapeutically manipulating lymphatic remodelling in disease.
Blue and green food webs respond differently to elevation and land use
Authors: Ho Hsi-Cheng , Brodersen Jakob , Gossner Martin M. , Graham Catherine H. , Kaeser Silvana , Chacko Merin Reji , Seehausen Ole , Zimmermann Niklaus E. , Pellissier Loïc , Altermatt Florian
Published: December 2021

While aquatic (blue) and terrestrial (green) food webs are parts of the same landscape, it remains unclear whether they respond similarly to shared environmental gradients. We use empirical community data from hundreds of sites across Switzerland, and show that blue and green food webs have different structural and ecological properties along elevation as a temperature proxy, and among various land-use types. Specifically, in green food webs, their modular structure increases with elevation and the overlap of consumers’ diet niche decreases, while the opposite pattern is observed in blue food webs. Such differences between blue and green food webs are particularly pronounced in farmland-dominated habitats, indicating that anthropogenic habitat modification moderates the climatic effects on food webs but differently in blue versus green systems. These findings indicate general structural differences between blue and green food webs and suggest their potential divergent future alterations through land use or climatic changes.
Dead infant carrying by chimpanzee mothers in the Budongo Forest
Authors: Soldati Adrian , Fedurek Pawel , Crockford Catherine , Adue Sam , Akankwasa John Walter , Asiimwe Caroline , Asua Jackson , Atayo Gideon , Chandia Boscou , Freymann Elodie , Fryns Caroline , Muhumuza Geresomu , Taylor Derry , Zuberbühler Klaus , Hobaiter Catherine
Published: December 2021

It has been suggested that non-human primates can respond to deceased conspecifics in ways that suggest they experience psychological states not unlike humans, some of which could indicate they exhibit a notion of death. Here, we report long-term demographic data from two East African chimpanzee groups. During a combined 40-year observation period we recorded 191 births of which 68 died in infancy, mostly within the first year. We documented the post-mortem behaviour of the mothers and describe nine occasions where Budongo chimpanzee mothers carried infants for 1-3 days after their death, usually until the body started to decompose. We also observed three additional cases of extended carrying lasting for more than two weeks, one of which was followed by the unusual extended carrying of an object and another which lasted three months. In each case, the corpses mummified. In addition, we report four instances of recurring dead infant carrying by mothers, three of whom carried the corpse for longer during the second instance. We discuss these observations in view of functional hypotheses of dead infant carrying in primates and the potential proximate mechanisms involved in this behaviour.
binny: an automated binning algorithm to recover high-quality genomes from complex metagenomic datasets
Authors: Hickl Oskar , Queirós Pedro , Wilmes Paul , May Patrick , Heintz-Buschart Anna
Published: December 2021

The reconstruction of genomes is a critical step in genome-resolved metagenomics and for multi-omic data integration from microbial communities. Here, we presentbinny, a binning tool that produces complete and pure metagenome-assembled genomes (MAG) from both contiguous and highly fragmented genomes. Based on established metrics,binnyoutperforms or is highly competitive with commonly-used and state- of-the-art binning methods and finds unique genomes that could not be detected by other methods.binnyuses k-mer-composition and coverage by metagenomic reads for iterative, non-linear dimension reduction of genomic signatures, as well as subsequent automated contig clustering with cluster assessment using lineage-specific marker gene sets. When compared to seven widely used binning algorithms,binnyprovides substantial amounts of uniquely identified MAGs and almost always recovers the most near-complete (>95% pure, >90% complete) and high-quality (>90% pure, >70% complete) genomes from simulated data sets from the Critical Assessment of Metagenome Interpretation (CAMI) initiative, as well as substantially more high-quality draft genomes, as defined by the Minimum Information about a Metagenome-Assembled Genome (MIMAG) standard, from a real-world benchmark comprised of metagenomes from various environments than any other tested method.
Image-based taxonomic classification of bulk biodiversity samples using deep learning and domain adaptation
Authors: Fujisawa Tomochika , Noguerales Víctor , Meramveliotakis Emmanouil , Papadopoulou Anna , Vogler Alfried P.
Published: December 2021

Complex bulk samples of invertebrates from biodiversity surveys present a great challenge for taxonomic identification, especially if obtained from unexplored ecosystems. High-throughput imaging combined with machine learning for rapid classification could overcome this bottleneck. Developing such procedures requires that taxonomic labels from an existing source data set are used for model training and prediction of an unknown target sample. Yet the feasibility of transfer learning for the classification of unknown samples remains to be tested. Here, we assess the efficiency of deep learning and domain transfer algorithms for family-level classification of below-ground bulk samples of Coleoptera from understudied forests of Cyprus. We trained neural network models with images from local surveys versus global databases of above-ground samples from tropical forests and evaluated how prediction accuracy was affected by: (a) the quality and resolution of images, (b) the size and complexity of the training set and (c) the transferability of identifications across very disparate source-target pairs that do not share any species or genera. Within-dataset classification accuracy reached 98% and depended on the number and quality of training images and on dataset complexity. The accuracy of between-datasets predictions was reduced to a maximum of 82% and depended greatly on the standardisation of the imaging procedure. When the source and target images were of similar quality and resolution, albeit from different faunas, the reduction of accuracy was minimal. Application of algorithms for domain adaptation significantly improved the prediction performance of models trained by non-standardised, low-quality images. Our findings demonstrate that existing databases can be used to train models and successfully classify images from unexplored biota, when the imaging conditions and classification algorithms are carefully considered. Also, our results provide guidelines for data acquisition and algorithmic development for high-throughput image-based biodiversity surveys.
Frequency transfer of the ventriloquism aftereffect
Authors: Ege Rachel , van Opstal A. John , van Wanrooij Marc M.
Published: December 2021

The ventriloquism aftereffect (VAE) describes the persistent shift of perceived sound location after having been adapted to a ventriloquism condition, in which the sound was repeatedly paired with a displaced visual stimulus. In the latter case, participants consistently mislocalize the sound in the direction of the visual stimulus (ventriloquism effect, VE). Previous studies provide conflicting reports regarding the strength of the VAE, ranging from 0 to nearly 100%. Moreover, there is controversy about its generalization to different sounds than the one inducing the VE, ranging from no transfer at all, to full transfer across different sound spectra. Here, we imposed the VE for three different sounds: a low-frequency and a high-frequency narrow-band noise, and a broadband Gaussian white noise (GWN). In the adaptation phase, listeners generated fast goal-directed head movements to localize the sound, presented across a 70 deg range in the horizontal plane, while ignoring a visual distracter that was consistently displaced 10 deg to the right of the sound. In the post-adaptation phase, participants localized narrow-band sounds with center frequencies from 0.5 to 8 kHz, as well as GWN, without the visual distracter. Our results show that the VAE amounted to approximately 40% of the VE and generalized well across the entire frequency domain. We also found that the strength of the VAE correlated with the pre-adaptation sound-localization performance. We compare our results with previous reports and discuss different hypotheses regarding optimal audio-visual cue integration.

Significance statement

Where we believe sounds to emanate from is heavily influenced by what we see. We experience this illusion - the ventriloquism effect - regularly. For example, when watching movies, we perceive the voices of actors to originate from the actors’ lips rather than from the speakers. Long exposure to a spatial mismatch between what we hear and what we see, leads to a recalibration of our localization of sounds - the ventriloquism aftereffect. Unclear was whether exposure to an audiovisual mismatch for one sound type would also lead to adaptive changes for other sounds. The present study shows that the ventriloquism aftereffect generalizes, implying that it does not act at an early auditory stage, but at a late multisensory stage.
Growth kinetics and power laws indicate distinct mechanisms of cell-cell interactions in the aggregation process
Authors: Mukhopadhyay Debangana , De Rumi
Published: December 2021

Cellular aggregation is a complex process orchestrated by various kinds of interactions depending on its environments. Different interactions give rise to different pathways of cellular rearrangement and the development of specialized tissues. To distinguish the underlying mechanisms, in this theoretical work, we investigate the spontaneous emergence of tissue patterns from an ensemble of single cells on a substrate following three leading pathways of cell-cell interactions, namely, direct cell adhesion contacts, matrix mediated mechanical interaction, and chemical signalling. Our analysis shows that the growth kinetics of the aggregation process is distinctly different for each pathway and bears the signature of the specific cell-cell interactions. Interestingly, we find that the average domain size and the mass of the clusters exhibit a power law growth in time under certain interaction mechanisms hitherto unexplored. Further, as observed in experiments, the cluster size distribution can be characterized by stretched exponential functions showing distinct cellular organization processes.
Opto-Katanin: An Optogenetic Tool for Localized Microtubule Disassembly
Authors: Meiring Joyce C. M. , Grigoriev Ilya , Nijenhuis Wilco , Kapitein Lukas C. , Akhmanova Anna
Published: December 2021

Microtubules are major cytoskeletal filaments that drive chromosome separation during cell division, serve as rails for intracellular transport and as a scaffold for organelle positioning. Experimental manipulation of microtubules is widely used in cell and developmental biology, but tools for precise subcellular spatiotemporal control of microtubule integrity are currently lacking. Here, we exploit the dependence of the mammalian microtubule-severing protein katanin on microtubule-targeting co-factors to generate a light-activated system for localized microtubule disassembly that we named opto-katanin. Targeted illumination with blue light induces rapid and localized opto-katanin recruitment and local microtubule depolymerization, which is quickly reversible after stopping light-induced activation. Opto-katanin can be employed to locally perturb microtubule-based transport and organelle morphology in dividing cells and differentiated neurons with high spatiotemporal precision. We show that different microtubule-associated proteins can be used to recruit opto-katanin to microtubules and induce severing, paving the way for spatiotemporally precise manipulation of specific microtubule subpopulations.
What do zebrafish prefer? Directional and color preferences in maze tasks
Authors: Marcon Matheus , Benvenutti Radharani , Gallas-Lopes Matheus , Herrmann Ana Paula , Piato Angelo
Published: December 2021

Studies regarding the animals’ innate preferences help elucidate and avoid probable sources of bias and serve as a reference to improve and develop new behavioral tasks. In zebrafish research, the results of innate directional and color preferences are often not replicated between research groups or even inside the same laboratory raising huge concerns on the replicability and reproducibility. Thus, this study aimed to investigate the male and female zebrafish innate directional and color preferences in the plus-maze and T-maze behavioral tasks. As revealed by the percentage of time spent in each zone of the maze, our results showed that males and females zebrafish demonstrated no difference in directional preference in the plus-maze task. Surprisingly, male and female zebrafish showed color preference differences in the plus-maze task; males did not show any color preference, while female zebrafish demonstrated a red preference compared to white, blue, and yellow colors. Moreover, both male and female zebrafish demonstrated a strong black color preference compared to the white color in the T-maze task. Thus, our results demonstrate the importance of innate preference assays involved with the directionality of the apparatus or the application of colors as a screening process conducting behavioral tests (e.g., anxiety, learning and memory assessment, locomotion, and preference) and highlight the need to analyze sex differences.
Transcriptome features of trained immunity in Drosophila
Authors: Fuse Naoyuki , Okamori Chisaki , Tang Chang , Hirai Kikuko , Okaji Ryoma , Kurata Shoichiro
Published: December 2021

Immune memory is an ability of organisms to potentiate immune responses at secondary infection. Current studies have revealed that innate immunity, as well as adaptive immunity, exhibits the memory character called “trained immunity”. Although it is suggested that epigenetic reprogramming plays important roles in trained immunity, its underlying mechanism is not fully understood, especially on the individual level.

Here we established experimental systems for detecting trained immunity in Drosophila melanogaster. Namely, training infection with low-pathogenic bacteria enhanced the survival rate of the flies at subsequent challenge infection with high-pathogenic bacteria. We found that among low-pathogenic bacteria, Micrococcus luteus (Ml) and Salmonella typhimurium (St) mediated apparent training effects in fly, but seemed to act through different ways. Ml left training effects even after its removal from flies, while living St persisted inside flies for a long time. Our RNA-Seq analysis revealed that Ml-training enhanced the expression of immune-related genes during the challenge infection, but did not do so without challenge infection. In contrast, St-training maintained high expression of the immune-related genes with or without challenge. These results suggest that training effects with Ml and St were due to memory and persistence of immune responses, respectively. Furthermore, we searched the factor involved in Ml-training and identified a candidate, Ada2b, which is a component of the histone modification complex. We found that the Ada2b RNAi and mutant flies showed dampened enhancement of survival rates after Ml-training. These results suggest that Ada2b is involved in the Drosophila trained immunity.
The ‘squalene route’ to carotenoid biosynthesis is widespread in Bacteria
Authors: Santana-Molina Carlos , Henriques Valentina , Hornero-Méndez Damaso , Devos Damien P. , Rivas-Marin Elena
Published: December 2021

Squalene is mostly associated with the biosynthesis of polycyclic triterpenes. Although there have been suggestions that squalene could be involved in the biosynthesis of carotenoids, functionally and evolutionarily related to polycyclic triterpenes, evidence of this ‘squalene route’ in nature was lacking. We demonstrate that planctomycetes synthesize C30 carotenoids via squalene and that this ‘squalene route’ is widely distributed in Bacteria. We also investigated the functional roles of hopanoids and carotenoids in Planctomycetes and show that their protective functions under stress conditions are complementary. Our evolutionary analyses suggest that the C30 carotenoid biosynthetic pathway is the most ancestral, with a potential origin in Firmicutes or Planctomycetes. In addition, we propose an evolutionary scenario to explain the diversification of the different carotenoid and squalene pathways. Together, these results improve the evolutionary contextualization of these molecules. Likewise, the widespread occurrence of the squalene route in bacteria increases the functional repertoire of squalene.
The transcription factor Zic4 acts as a transdifferentiation switch
Authors: Vogg Matthias Christian , Ferenc Jaroslav , Buzgariu Wanda Christa , Perruchoud Chrystelle , Papasaikas Panagiotis , Sanchez Paul Gerald Layague , Nuninger Clara , Delucinge-Vivier Céline , Rampon Christine , Beccari Leonardo , Vriz Sophie , Vincent Stéphane , Galliot Brigitte , Tsiairis Charisios D.
Published: December 2021

The molecular mechanisms that maintain cell identities and prevent transdifferentiation remain mysterious. Interestingly, both dedifferentiation and transdifferentiation are transiently reshuffled during regeneration. Therefore, organisms that regenerate readily offer a fruitful paradigm to investigate the regulation of cell fate stability. Here, we used Hydra as a model system and show that Zic4 silencing is sufficient to induce transdifferentiation of tentacle into foot cells. We identified a Wnt-controlled Gene Regulatory Network that controls a transcriptional switch of cell identity. Furthermore, we show that this switch also controls the re-entry into the cell cycle. Our data indicate that maintenance of cell fate by a Wnt-controlled GRN is a key mechanism during both homeostasis and regeneration.

One-Sentence Summary

A Wnt-controlled GRN controls fate maintenance in Hydra.
Transport receptor occupancy in Nuclear Pore Complex mimics
Authors: Fragasso Alessio , de Vries Hendrik W. , Andersson John , van der Sluis Eli O. , van der Giessen Erik , Onck Patrick R. , Dekker Cees
Published: December 2021

Nuclear Pore Complexes (NPCs) regulate all molecular transport between the nucleus and the cytoplasm in eukaryotic cells. Intrinsically disordered Phe-Gly nucleoporins (FG Nups) line the central conduit of NPCs to impart a selective barrier where large proteins are excluded unless bound to a transport receptor (karyopherin; Kap). Here, we assess ‘Kap-centric’ NPC models, which postulate that Kaps participate in establishing the selective barrier. We combine biomimetic nanopores, formed by tethering Nsp1 to the inner wall of a solid-state nanopore, with coarse-grained modeling to show that yeast Kap95 exhibits two populations in Nsp1-coated pores: one population that is transported across the pore in milliseconds, and a second population that is stably assembled within the FG mesh of the pore. Ionic current measurements show a conductance decrease for increasing Kap concentrations and noise data indicate an increase in rigidity of the FG-mesh. Modeling reveals an accumulation of Kap95 near the pore wall, yielding a conductance decrease. We find that Kaps only mildly affect the conformation of the Nsp1 mesh and that, even at high concentrations, Kaps only bind at most 8% of the FG-motifs in the nanopore, indicating that Kap95 occupancy is limited by steric constraints rather than by depletion of available FG-motifs. Our data provide an alternative explanation of the origin of bimodal NPC binding of Kaps, where a stable population of Kaps binds avidly to the NPC periphery, while fast transport proceeds via a central FG-rich channel through lower affinity interactions between Kaps and the cohesive domains of Nsp1.
The impact of low input DNA on the reliability of DNA methylation as measured by the Illumina Infinium MethylationEPIC BeadChip
Authors: Watkins Sarah Holmes , Ho Karen , Testa Christian , Falk Louise , Soule Patrice , Nguyen Linda V. , FitzGibbon Sophie , Slack Catherine , Chen Jarvis T. , Smith George Davey , De Vivo Immaculata , Simpkin Andrew J. , Tilling Kate , Waterman Pamela D. , Krieger Nancy , Suderman Matthew , Relton Caroline
Published: December 2021

Background

DNA methylation (DNAm) is commonly assayed using the Illumina Infinium MethylationEPIC BeadChip, but there is currently little published evidence to define the lower limits of the amount of DNA that can be used whilst preserving data quality. Such evidence is valuable for analyses utilising precious or limited DNA sources.

Materials and methods

We use a single pooled sample of DNA in quadruplicate at three dilutions to define replicability and noise, and an independent population dataset of 328 individuals (from a community-based study including US-born non-Hispanic Black and white persons) to assess the impact of total DNA input on the quality of data generated using the Illumina Infinium MethylationEPIC BeadChip.

Results

Data are less reliable and more noisy as DNA input decreases to 40ng, with clear reductions in data quality; however samples with a total input as low as 40ng pass standard quality control tests, and we observe little evidence that low input DNA obscures the associations between DNAm and two phenotypes, age and smoking status.

Conclusions

DNA input as low as 40ng can be used with the Illumina Infinium MethylationEPIC BeadChip, provided quality checks and sensitivity analyses are undertaken.