bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zetaproteobacteria pan-genome reveals candidate gene cluster for twisted stalk biosynthesis and export
Authors: Koeksoy E. , Bezuidt O.M. , Bayer T. , Chan C.S. , Emerson D. 
Published: March 2021

AbstractTwisted stalks are morphologically unique bacterial extracellular organo-metallic structures containing Fe(III) oxyhydroxides that are produced by microaerophilic Fe(II)-oxidizers belonging to the Betaproteobacteria and Zetaproteobacteria. Understanding the underlying genetic and physiological mechanisms of stalk formation is of great interest based on their potential as novel biogenic nanomaterials and their relevance as putative biomarkers for microbial Fe(II) oxidation on ancient Earth. Despite the recognition of these special biominerals for over 150 years, the genetic foundation for the stalk phenotype has remained unresolved. Here we present a candidate gene cluster for the biosynthesis and secretion of the stalk organic matrix that we identified with a trait-based analyses of a pan-genome comprising 16 Zetaproteobacteria isolate genomes. The “stalkformation inZetaproteobacteria” (sfz) cluster comprises six genes (sfz1-sfz6), of whichsfz1andsfz2were predicted with functions in exopolysaccharide synthesis, regulation, and export,sfz4andsfz6with functions in cell wall synthesis manipulation and carbohydrate hydrolysis, andsfz3andsfz5with unknown functions. The stalk-forming BetaproteobacteriaFerriphaselusR-1 and OYT-1, as well as dread-forming ZetaproteobacteriaMariprofundus aestuariumCP-5 andMariprofundus ferrinatatusCP-8 contain distantsfzgene homologues, whereas stalk-less Zetaproteobacteria and Betaproteobacteria lack the entire gene cluster. Our pan-genome analysis further revealed a significant enrichment of clusters of orthologous groups (COGs) across all Zetaproteobacteria isolate genomes that are associated with the regulation of a switch between sessile and motile growth controlled by the intracellular signaling molecule c-di-GMP. Potential interactions between stalk-former unique transcription factor genes,sfzgenes, and c-di-GMP point towards a c-di-GMP regulated surface attachment function of stalks during sessile growth.
Drug-bound and -free outward-facing structures of a multidrug ABC exporter point to a swing mechanism
Authors: Chaptal Vincent , Zampieri Veronica , Wiseman Benjamin , Orelle Cédric , Martin Juliette , Nguyen Kim-Anh , Magnard Sandrine , Gobet Alexia , Cesare Margot Di , Javed Waqas , Kilburg Arnaud , Peuchmaur Marine , Marcoux Julien , Monticelli Luca , Högbom Martin , Jault Jean-Michel , Boumendjel Ahcène , Falson Pierre 
Published: March 2021

AbstractMultidrug ABC transporters translocate drugs across membranes by a mechanism for which the molecular features of drug release are so far unknown. Here, we resolved two ATP-Mg2+-bound outward-facing (OF) conformations of theBacillus subtilis(homodimeric) BmrA, one by X-ray crystallography without drug, and another by single-particle cryo-EM with rhodamine 6G (R6G). Two R6G molecules bind to the drug-binding cavity at the level of the outer leaflet, between transmembrane (TM) helices 1-2 of one monomer and TM5’-6’ of the other. R6G induces a rearrangement of TM1-2, highlighting a flexibility that was confirmed by H/D exchange and molecular dynamics simulations. The latter also shows a fast post-release occlusion of the cavity driven by hydrophobicity. Altogether, these data support a new swing mechanism for drug transport.
Joint inference of adaptive and demographic history from temporal population genomic data
Authors: Pavinato Vitor A. C. , De Mita Stéphane , Marin Jean-Michel , de Navascués Miguel 
Published: March 2021

AbstractDisentangling the effects of selection and drift is a long-standing problem in population genetics. Simulations show that pervasive selection may bias the inference of demography. Ideally, models for the inference of demography and selection should account for the interaction between these two forces. With simulation-based likelihood-free methods such as Approximate Bayesian Computation (ABC), demography and selection parameters can be jointly estimated. We propose to use the ABC-Random Forests framework to jointly infer demographic and selection parameters from temporal population genomic data (e.g. experimental evolution, monitored populations, ancient DNA). Our framework allowed the separation of demography (census size,N) from the genetic drift (effective population size,Ne) and the estimation of genome-wide parameters of selection. Selection parameters informed us about the adaptive potential of a population (the scaled mutation rate of beneficial mutations,θb), the realized adaptation (the number of mutation under strong selection), and population fitness (genetic load). We applied this approach to a dataset of feral populations of honey bees (Apis mellifera) collected in California, and we estimated parameters consistent with the biology and the recent history of this species.
Endomitosis controls tissue-specific gene expression during development
Authors: van Rijnberk Lotte M , van der Palen Reinier L , Schild Erik S , Korswagen Hendrik C , Galli Matilde 
Published: March 2021

SummaryPolyploid cells contain more than two copies of the genome and are found in many plant and animal tissues. Different types of polyploidy exist, in which the genome is confined to either one nucleus (mononucleation) or two or more nuclei (multinucleation). Despite the widespread occurrence of polyploidy, the functional significance of different types of polyploidy are largely unknown. Here, we assess the function of multinucleation inC. elegansintestinal cells through specific inhibition of binucleation without altering genome ploidy. Through single worm RNA sequencing, we find that binucleation is important for tissuespecific gene expression, most prominently for genes that show a rapid upregulation at the transition from larval development to adulthood. Regulated genes include vitellogenins, which encode yolk proteins that facilitate nutrient transport to the germline. We find that reduced expression of vitellogenins in mononucleated intestinal cells leads to progeny with developmental delays and reduced fitness. Together, our results show that binucleation facilitates rapid upregulation of intestine-specific gene expression during development, independently of genome ploidy, underscoring the importance of spatial genome organization for polyploid cell function.
The PPR domain of mitochondrial RNA polymerase is a ribonuclease required for mtDNA replication
Authors: Liu Yi , Chen Zhe , Wang Zong-Heng , Delaney Katherine , Tang Juanjie , Pirooznia Mehdi , Lee Duck-Yeon , Li Yuesheng , Xu Hong 
Published: March 2021

AbstractMitochondrial DNA (mtDNA) replication and transcription are of paramount importance to cellular energy metabolism. Mitochondrial RNA polymerase (POLRMT) is thought to be the primase for mtDNA replication. However, it is unclear how POLRMT, which normally transcribes long polycistronic RNAs, can produce short RNA oligos to initiate mtDNA replication. Here we show that the PPR domain ofDrosophilaPOLRMT is a 3’ to 5’ exoribonuclease. The exoribonuclease activity is indispensable for POLRMT to synthesize short RNA oligos and to prime DNA replicationin vitro. An exoribonuclease deficient POLRMT, POLRMTE423Ppartially restores mitochondrial transcription but fails to support mtDNA replication when expressed inPOLRMTmutant background, indicating that the exoribonuclease activity is necessary for mtDNA replication. Overexpression of POLRMTE423Pin adult flies leads to severe neuromuscular defects and a marked increase of mtDNA transcripts errors, suggesting that exoribonuclease activity may contribute to the proofreading of mtDNA transcription. PPR domain of human POLRMT also has exoribonuclease activity, indicating evolutionarily conserved roles of PPR domain in mitochondrial DNA and RNA metabolism.
Hippocampal and thalamic afferents form distinct synaptic microcircuits in the mouse frontal cortex
Authors: Graham Kourtney , Spruston Nelson , Bloss Erik B. 
Published: March 2021

AbstractNeural circuits within the frontal cortex support the flexible selection of goal-directed behaviors by integrating input from brain regions associated with sensory, emotional, episodic, and semantic memory functions. From a connectomics perspective, determining how these disparate afferent inputs target their synapses to specific cell types in the frontal cortex may prove crucial in understanding circuit-level information processing. Here, we used monosynaptic retrograde rabies mapping to examine the distribution of afferent neurons targeting four distinct classes of local inhibitory interneurons and four distinct classes of excitatory projection neurons in mouse infralimbic cortex. Interneurons expressing parvalbumin, somatostatin, or vasoactive intestinal peptide received a large proportion of inputs from hippocampal regions, while interneurons expressing neuron-derived neurotrophic factor received a large proportion of inputs from thalamic regions. A more moderate hippocampal-thalamic dichotomy was found among the inputs targeting excitatory neurons that project to the basolateral amygdala, lateral entorhinal cortex, nucleus reuniens of the thalamus, and the periaqueductal gray. Together, these results show a prominent bias among hippocampal and thalamic afferent systems in their targeting to genetically or anatomically defined sets of frontal cortical neurons. Moreover, they suggest the presence of two distinct local microcircuits that control how different inputs govern frontal cortical information processing.
Social Selection and the Evolution of Maladaptation
Authors: McGlothlin Joel W. , Fisher David N. 
Published: March 2021

AbstractEvolution by natural selection is often viewed as a process that inevitably leads to adaptation, or an increase in population fitness over time. However, maladaptation, an evolved decrease in fitness, may also occur in response to natural selection under some conditions. Social selection, which arises from the effects of social partners on fitness, has been identified as a potential cause of maladaptation, but we lack a general rule identifying when social selection should lead to a decrease in population mean fitness. Here we use a quantitative genetic model to develop such a rule. We show that maladaptation is most likely to occur when social selection is strong relative to nonsocial selection and acts in an opposing direction. In this scenario, the evolution of traits that impose fitness costs on others may outweigh evolved gains in fitness for the individual, leading to a net decrease in population mean fitness. Further, we find that maladaptation may also sometimes occur when phenotypes of interacting individuals negatively covary. We outline the biological situations where maladaptation in response to social selection can be expected, provide both quantitative genetic and phenotypic versions of our derived result, and suggest what empirical work would be needed to test it. We also consider the effect of social selection on inclusive fitness and support previous work showing that inclusive fitness cannot suffer an evolutionary decrease. Taken together, our results show that social selection may decrease population mean fitness when it opposes individual-level selection, even as inclusive fitness increases.Subject areaQuantitative genetics and Mendelian inheritance
Ca2+-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair
Authors: Niekamp Patrick , Sokoya Tolulope , Vittadello Laura , Deng Yongqiang , Kim Yeongho , Hilderink Angelika , Imlau Mirco , Clarke Christopher J. , Burd Christopher G. , Holthuis Joost C. M. 
Published: March 2021

AbstractLysosomes are vital organelles vulnerable to injuries from diverse materials. Failure to repair or sequester damaged lysosomes poses a threat to cell viability. Here we report that cells exploit a sphingomyelin-based lysosomal repair pathway that operates independently of ESCRT to reverse potentially lethal membrane damage. Various conditions perturbing organelle integrity trigger a rapid calcium-activated scrambling and cytosolic exposure of sphingomyelin. Subsequent metabolic conversion of sphingomyelin by neutral sphingomyelinases on the cytosolic surface of injured lysosomes promotes their repair, also when ESCRT function is compromised. Conversely, blocking turnover of cytosolic sphingomyelin renders cells more sensitive to lysosome-damaging drugs. Our data indicate that calcium-activated scramblases, sphingomyelin, and neutral sphingomyelinases are core components of a previously unrecognized membrane restoration pathway by which cells preserve the functional integrity of lysosomes.
Natural genetic variation drives microbiome selection in theCaenorhabditis elegansgut
Authors: Zhang Fan , Weckhorst Jessica L. , Assié Adrien , Hosea Ciara , Ayoub Christopher A. , Khodakova Anastasia , Cabrera Mario Loeza , Vidal Daniela , Félix Marie-Anne , Samuel Buck S. 
Published: March 2021

SUMMARYHost genetic landscapes can shape microbiome assembly in the animal gut by contributing to the establishment of distinct physiological environments. However, the genetic determinants contributing to the stability and variation of these microbiome types remain largely undefined. Here, we use the free-living nematodeCaenorhabditis elegansto identify natural genetic variation among wild strains ofC. elegansstrains that drives assembly of distinct microbiomes. To achieve this, we first established a diverse model microbiome that represents the phylogenetic and functional diversity naturally found in theC. elegansmicrobiome. Using this community, we show thatC. elegansutilizes immune, xenobiotic and metabolic signaling pathways to favor the assembly of different microbiome types. Variations in these pathways were associated with the enrichment for specific commensals, including the AlphaproteobacteriaOchrobactrum. Using RNAi and mutant strains, we showed that host selection forOchrobactrumis mediated specifically by host insulin signaling pathways.Ochrobactrumrecruitment is blunted in the absence ofdaf-2/IGFR and requires the insulin signaling transcription factorsdaf-16/FOXO andpqm-1/SALL2. Further, the ability ofC. elegansto enrich forOchrobactrumis correlated positively with host outcomes, as animals that develop faster are larger and have higher gutOchrobactrumcolonization as adults. These results highlight a new role for the highly conserved insulin signaling pathways in the regulation of microbiome composition inC. elegans.
Electro-Metabolic Sensing Through Capillary ATP-Sensitive K+Channels and Adenosine to Control Cerebral Blood Flow
Authors: Sancho Maria , Klug Nicholas R. , Mughal Amreen , Heppner Thomas J. , Hill-Eubanks David , Nelson Mark. T. 
Published: March 2021

SUMMARYThe dense network of capillaries composed of capillary endothelial cells (cECs) and pericytes lies in close proximity to all neurons, ideally positioning it to sense neuro/glial-derived compounds that regulate regional and global cerebral perfusion. The membrane potential (VM) of vascular cells serves as the essential output in this scenario, linking brain activity to vascular function. The ATP-sensitive K+channel (KATP) is a key regulator of vascular VMin other beds, but whether brain capillaries possess functional KATPchannels remains unknown. Here, we demonstrate that brain capillary ECs and pericytes express KATPchannels that robustly control VM. We further show that the endogenous mediator adenosine acts through A2Areceptors and the Gs/cAMP/PKA pathway to activate capillary KATPchannels. Moreover, KATPchannel stimulationin vivocauses vasodilation and increases cerebral blood flow (CBF). These findings establish the presence of KATPchannels in cECs and pericytes and suggest their significant influence on CBF.HIGHLIGHTSCapillary network cellular components—endothelial cells and pericytes—possess functional KATPchannels.Activation of KATPchannels causes profound hyperpolarization of capillary cell membranes.Capillary KATPchannels are activated by exogenous adenosine via A2Areceptors and cAMP-dependent protein kinase.KATPchannel activation by adenosine or synthetic openers increases cerebral blood flow.
DNA methylation is not a driver of gene expression reprogramming in young honey bee workers
Authors: Cardoso-Junior Carlos A. M. , Yagound Boris , Ronai Isobel , Remnant Emily J. , Hartfelder Klaus , Oldroyd Benjamin P. 
Published: March 2021

AbstractIntragenic DNA methylation, also called gene body methylation, is an evolutionarily-conserved epigenetic mechanism in animals and plants. In social insects, gene body methylation is thought to contribute to behavioral plasticity, for example between foragers and nurse workers, by modulating gene expression. However, recent studies have suggested that the majority of DNA methylation is sequence-specific, and therefore cannot act as a flexible mediator between environmental cues and gene expression. To address this paradox, we examined whole-genome methylation patterns in the brains and ovaries of young honey bee workers that had been subjected to divergent social contexts: the presence or absence of the queen. Although these social contexts are known to bring about extreme changes in behavioral and reproductive traits through differential gene expression, we found no significant differences between the methylomes of workers from queenright and queenless colonies. In contrast, thousands of regions were differentially methylated between colonies, and these differences were not associated with differential gene expression in a subset of genes examined. Methylation patterns were highly similar between brain and ovary tissues and only differed in nine regions. These results strongly indicate that DNA methylation is not a driver of differential gene expression between tissues or behavioral morphs. Finally, despite the lack of difference in methylation patterns, queen presence affected the expression of all four DNA methyltransferase genes, suggesting that these enzymes have roles beyond DNA methylation. Therefore, the functional role of DNA methylation in social insect genomes remains an open question.
An extended DNA-free intranuclear compartment organizes centrosomal microtubules in Plasmodium falciparum
Authors: Simon Caroline S. , Funaya Charlotta , Bauer Johanna , Voß Yannik , Machado Marta , Penning Alexander , Klaschka Darius , Cyrklaff Marek , Kim Juyeop , Ganter Markus , Guizetti Julien 
Published: March 2021

AbstractRapid proliferation ofPlasmodium falciparumparasites in human red blood cells is the cause of malaria and is underpinned by an unconventional cell division mode, called schizogony. Contrary to model organisms,P. falciparumreplicates by multiple rounds of closed and asynchronous nuclear divisions that are not interrupted by cytokinesis. Organization and dynamics of the critical nuclear division factors are, however, poorly understood. Centriolar plaques, the centrosomes ofP. falciparum, are important regulators of division and serve as microtubule organizing centers. Early microscopy studies reveal an acentriolar, amorphous structure although its detailed organization remains elusive. Intranuclear microtubules mediate chromosome segregation, but the small size of parasite nuclei has precluded detailed analysis of their arrangement by classical fluorescence microscopy. We apply recently developed STED, expansion microscopy, and live cell imaging protocols to describe the reconfiguration of microtubules during schizogony. Analysis of centrin, nuclear pore, and microtubule positioning reveals a bipartite organization of the centriolar plaque. While centrin is extranuclear, we confirm by correlative light and electron tomography that microtubules are nucleated in a previously unknown and extended intranuclear compartment, which is devoid of chromatin. This study enables us to build a working model of the organization of an unconventional centrosome and better understand the diversity of eukaryotic cell division modes.
Can offsetting the energetic cost of hibernation restore an active season phenotype in grizzly bears (Ursus arctos horribilis)?
Authors: Jansen Heiko T. , Hutzenbiler Brandon Evans , Hapner Hannah R. , McPhee Madeline L. , Carnahan Anthony M. , Kelley Joanna L. , Saxton Michael W. , Robbins Charles T. 
Published: March 2021

ABSTRACTHibernation is characterized by suppression of many physiological processes. To determine if this state is reversible in a non-food caching species, we fed hibernating grizzly bears (Ursus arctos horribilis) glucose for 10 days to replace 53% or 100% of the estimated minimum daily energetic cost of hibernation. Feeding caused serum concentrations of glycerol and ketones (ß-hydroxybutyrate) to return to active season levels irrespective of the amount of glucose fed. By contrast, free-fatty acids and indices of metabolic rate, such as general activity, heart rate, and strength of the daily heart rate rhythm and insulin sensitivity were restored to roughly 50% of active season levels. Body temperature was unaffected by feeding. To determine the contribution of adipose to these metabolic effects of glucose feeding we cultured bear adipocytes collected at the beginning and end of the feeding and performed metabolic flux analysis. We found a roughly 33% increase in energy metabolism after feeding. Moreover, basal metabolism before feeding was 40% lower in hibernation cells compared to fed cells or active cells cultured at 37°C, thereby confirming the temperature independence of metabolic rate. The partial suppression of circulating FFA with feeding likely explains the incomplete restoration of insulin sensitivity and other metabolic parameters in hibernating bears. Further suppression of metabolic function is likely an active process. Together, the results provide a highly controlled model to examine the relationship between nutrient availability and metabolism on the hibernation phenotype in bears.
Neural Networks for parameter estimation in microstructural MRI: a study with a high-dimensional diffusion-relaxation model of white matter microstructure
Authors: de Almeida Martins João P. , Nilsson Markus , Lampinen Björn , Palombo Marco , While Peter T. , Westin Carl-Fredrik , Szczepankiewicz Filip 
Published: March 2021

ABSTRACTSpecific features of white-matter microstructure can be investigated by using biophysical models to interpret relaxation-diffusion MRI brain data. Although more intricate models have the potential to reveal more details of the tissue, they also incur time-consuming parameter estimation that may con-verge to inaccurate solutions due to a prevalence of local minima in a degenerate fitting landscape. Machine-learning fitting algorithms have been proposed to accelerate the parameter estimation and increase the robustness of the attained estimates. So far, learning-based fitting approaches have been restricted to lower-dimensional microstructural models where dense sets of training data are easy to generate. Moreover, the degree to which machine learning can alleviate the degeneracy problem is poorly understood. For conventional least-squares solvers, it has been shown that degeneracy can be avoided by acquisition with optimized relaxation-diffusion-correlation protocols that include tensor-valued diffusion encoding; whether machine-learning techniques can offset these acquisition require-ments remains to be tested. In this work, we employ deep neural networks to vastly accelerate the fitting of a recently introduced high-dimensional relaxation-diffusion model of tissue microstructure. We also develop strategies for assessing the accuracy and sensitivity of function fitting networks and use those strategies to explore the impact of acquisition protocol design on the performance of the network. The developed learning-based fitting pipelines were tested on relaxation-diffusion data acquired with optimized and sub-sampled acquisition protocols. We found no evidence that machine-learning algorithms can by themselves replace a careful design of the acquisition protocol or correct for a degenerate fitting landscape.