bluuebunny/crossref_metadata_2025 huggingface dataset:
KS-WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates
Authors: Boyd-Shiwarski Cary R. , Beacham Rebecca T. , Lashway Jared A. , Querry Katherine E. , Griffiths Shawn E. , Shiwarski Daniel J. , Knoell Sophia A. , Nguyen Nga H. , Nkashama Lubika J. , Valladares Melissa N. , Bandaru Anagha , Marciszyn Allison L. , Rodan Aylin R. , Huang Chou-Long , Stocker Sean D. , Kashlan Ossama B. , Subramanya Arohan R.
Published: March 2021

To maintain potassium homeostasis, the kidney’s distal convoluted tubule (DCT) converts small changes in blood [K+] into robust effects on salt reabsorption. This process requires NaCl cotransporter (NCC) activation by WNK kinases. During hypokalemia, the Kidney-Specific WNK1 isoform (KS-WNK1) scaffolds the DCT-expressed WNK signaling pathway within biomolecular condensates of unknown function termed WNK bodies. Here, we show that KS-WNK1 amplifies the dynamic range of NCC activity in response to potassium imbalance, in part via WNK bodies. Targeted condensate disruption traps the WNK pathway, causing renal salt-wasting that is more pronounced in females. In humans, WNK bodies accumulate as plasma potassium falls below 4.0mmol/L, suggesting avid condensate-mediated salt reabsorption even when [K+] is low-normal. These data identify WNK bodies as signal amplifiers that mediate tubular potassium responsiveness, nephron sexual dimorphism, and blood pressure salt-sensitivity. Our results illustrate how condensate specialization can optimize a mammalian physiologic stress response that impacts human health.
Management programs as a key factor for genetic conservation of small populations : The case of French local chicken breeds
Authors: Restoux Gwendal , Rognon Xavier , Vieaud Agathe , Guemene Daniel , Petitjean Florence , Rouger Romuald , Brard-Fudulea Sophie , Lubac-Paye Sophie , Chiron Geoffrey , Tixier-Boichard Michèle
Published: March 2021

On-going climate change will drastically modify agriculture in the future, with a need for more sustainable systems, for animal production in particular. In this context, genetic diversity is a key factor for adaptation to new conditions: local breeds are likely to harbor unique adaptive features and represent a key component of diversity to reach resilience. Nevertheless, they are often suffering from small population size putting these valuable resources at risk of extinction. In chickens, management programs have been initiated a few decades ago in France, relying on a particular niche market aiming at promoting and protecting local breeds. We conducted a unique comprehensive study of 23 French local populations, along with 4 commercial lines, to evaluate their genetic conservation status and the efficiency of management programs. Using a 57K SNP chip we demonstrated that both between and within breeds genetic diversity were high in French populations. Diversity was mainly structured according to selection and breeds’ history. Nevertheless, we observed a prominent sub-structuring of breeds according to farmer’s practices in terms of exchange, leading to more or less isolated flocks. Analysing demographic parameters as well as molecular information, we showed the efficiency of consistent management programs to conserve genetic diversity, since the earlier the breeds integrated programs the lower was the inbreeding. Finally we stressed that management programs can benefit from molecular markers and runs of homozygosity, ROH, in particular, as a valuable and affordable tool to monitor genetic diversity of local breeds which often lack pedigree information.
Evolution of class-structured populations in periodic environments
Authors: Lion Sébastien , Gandon Sylvain
Published: March 2021

What is the influence of periodic environmental fluctuations on life-history evolution? We present a general theoretical framework to understand and predict the long-term evolution of lifehistory traits under a broad range of ecological scenarios. Specifically, we investigate how periodic fluctuations affect selection when the population is also structured in distinct classes. This analysis yields time-varying selection gradients that clarify the influence of the fluctuations of the environment on the competitive ability of a specific life-history mutation. We use this framework to analyse the evolution of key life-history traits of pathogens. We examine three different epidemiological scenarios and we show how periodic fluctuations of the environment can affect the evolution of virulence and transmission as well as the preference for different hosts. These examples yield new and testable predictions on pathogen evolution, and illustrate how our approach can provide a better understanding of the evolutionary consequences of time-varying environmental fluctuations in a broad range of scenarios.
A Fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway ofMycobacterium tuberculosis
Authors: Gupta Pooja , Thomas Sherine E. , Cory-Wright James , Sebastián-Pérez Víctor , Burgess Ailidh , Cattermole Emma , Meghir Clio , Abell Chris , Coyne Anthony G. , Jacobs William R. , Blundell Tom L. , Tiwari Sangeeta , Mendes Vítor
Published: March 2021

The L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine, appears to be attractive target for anti-Tuberculosis (TB) drug discovery. Starvation ofM.tuberculosis deleted for eitherargBorargFgenes led to rapid sterilization of these strains in mice while Chemical inhibition of ArgJ with Pranlukast was also found to clear chronicM. tuberculosisinfection in animal models. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is explored using a fragment-based approach. We reveal several hits for these enzymes validated with biochemical and biophysical assays, and X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity againstM. tuberculosis. These results demonstrate the potential of more enzymes in this pathway to be targeted with dedicated drug discovery programmes.
Introspection confidence predicts EEG decoding of self-generated thoughts and meta-awareness
Authors: Polychroni Naya , Ruiz Maria Herrojo , Terhune Devin B.
Published: March 2021

The neurophysiological bases of mind wandering (MW) – an experiential state wherein attention is disengaged from the external environment in favour of internal thoughts, and state meta-awareness are poorly understood. In parallel, the relationship between introspection confidence in experiential state judgements and neural representations remains unclear. Here, we recorded EEG whilst participants completed a listening task within which they made experiential state judgments and rated their confidence. Alpha power was reliably greater during MW episodes, with unaware MW further associated with greater delta and theta power. Multivariate pattern classification analysis revealed that MW, and meta-awareness can be decoded from the distribution of power in these three frequency bands. Critically, we show that individual decoding accuracies positively correlate with introspection confidence. Our results reaffirm the role of alpha oscillations in MW, implicate lower frequencies in meta-awareness, and are consistent with the proposal that introspection confidence indexes neurophysiological discriminability of representational states.
Measuring context-dependent memory in rodents: a systematic review and meta-analysis of important variables in the object-in-context task
Authors: Sep Milou S.C. , Vellinga Marijn , Sarabdjitsingh R. Angela. , Joëls Marian
Published: March 2021

Environmental information plays an important role in remembering events. Information about stable aspects of the environment (here referred to as ‘context’) and the event are combined by the hippocampal system and stored as context-dependent memory. In rodents (such as rats and mice), context-dependent memory is often investigated with the object-in-context task. However, the implementation and interpretation of this task varies considerably across studies. This variation hampers the comparison between studies and - for those who design a new experiment or carry out pilot experiments – the estimation of whether observed behavior is within the expected range. Also, it is currently unclear which of the variables critically influence the outcome of the task. To address these issues, we carried out a preregistered systematic review (PROSPERO CRD42020191340) and provide an up-to-date overview of the animal-, task-, and protocol-related variations in the object-in-context task for rodents. Using a data-driven explorative meta-analysis we next identified critical factors influencing the outcome of this task, such as sex, testbox size and the delay between the learning trials. Based on these observations we provide recommendations to create more consensus in the set-up, procedure and interpretation of the object-in-context task for rodents. This could contribute to a more robust and evidence-based design in future animal experiments.
Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor inCaenorhabditis elegans
Authors: Feng Dingxia , Zhai Zhiwei , Shao Zhiyong , Zhang Yi , Powell-Coffman Jo Anne
Published: March 2021

During development, homeostasis, and disease, organisms must balance responses that allow adaptation to low oxygen (hypoxia) with those that protect cells from oxidative stress. The evolutionarily conserved hypoxia-inducible factors are central to these processes, as they orchestrate transcriptional responses to oxygen deprivation. Here, we employ genetic strategies inC. elegansto identify stress-responsive genes and pathways that modulate the HIF-1 hypoxia-inducible factor and facilitate oxygen homeostasis. Through a genome-wide RNAi screen, we show that RNAi-mediated mitochondrial or proteasomal dysfunction increases the expression of hypoxia-responsive reporterPnhr-57:GFPinC. elegans.Interestingly, only a subset of these effects requireshif-1.Of particular importance, we found thatskn-1RNAi increases the expression of hypoxia-responsive reporterPnhr-57:GFPand elevates HIF-1 protein levels. The SKN-1/NRF transcription factor has been shown to promote oxidative stress resistance. We present evidence that the crosstalk between HIF-1 and SKN-1 is mediated by EGL-9, the prolyl hydroxylase that targets HIF-1 for oxygen-dependent degradation. Treatment that induces SKN-1, such as heat, increases expression of aPegl-9:GFPreporter, and this effect requiresskn-1function and a putative SKN-1 binding site inegl-9regulatory sequences. Collectively, these data support a model in which SKN-1 promotesegl-9transcription, thereby inhibiting HIF-1. We propose that this interaction enables animals to adapt quickly to changes in cellular oxygenation and to better survive accompanying oxidative stress.
Yeast proteins reversibly aggregate like amphiphilic molecules
Authors: Dasmeh Pouria , Wagner Andreas
Published: March 2021

More than a hundred proteins in yeast reversibly aggregate and phase-separate in response to various stressors, such as nutrient depletion and heat shock. We know little about the sequence and structural features behind this ability, which has not been characterized on a proteome-wide level. To identify the distinctive features of aggregation-prone regions, we apply machine learning algorithms to genome-scale limited proteolysis-mass spectrometry data from 96 yeast proteins that phase-separate upon heat shock. We find that the aggregation-prone regions (APRs) of our study proteins are significantly enriched in aliphatic residues and depleted in positively charged amino acids. Aggregator proteins with longer APRs show a greater propensity to aggregate, a relationship that can be explained by equilibrium statistical thermodynamics. Altogether, our observations suggest that proteome-wide reversible protein aggregation is mediated by sequence-encoded properties. Aggregating proteins resemble supra-molecular amphiphiles, where APRs are the hydrophobic parts, and non-APRs are the hydrophilic parts.
DNA methylome-based validation of induced sputum as an effective protocol to study lung immunity: construction of a classifier of pulmonary cell types
Authors: Das Jyotirmoy , Idh Nina , Sikkeland Liv Ingunn Bjoner , Paues Jakob , Lerm Maria
Published: March 2021

Background

Flow cytometry is a classical approach used to define cell types in peripheral blood. While DNA methylation signatures have been extensively employed in recent years as an alternative to flow cytometry to define cell populations in peripheral blood, this approach has not been tested in lung-derived samples. Here, we compared bronchoalveolar lavage with a more cost-effective and less invasive technique based on sputum induction and developed a DNA methylome-based algorithm that can be used to deconvolute the cell types in such samples.

Results

We analyzed the DNA methylome profiles of alveolar macrophages and lymphocytes cells isolated from the pulmonary compartment. The cells were isolated using two different methods, sputum induction and bronchoalveolar lavage. A strong positive correlation between the DNA methylome profiles of cells obtained with the two isolation methods was observed, and in two of the donors, in which the correlation was best, a later analyses demonstrated that those subjects the samples were consistently derived from the lower part of the lungs. We also identified unique patterns of CpG methylation in DNA obtained from the two cell populations, which can be used as a signature to discriminate between the alveolar macrophages and lymphocytes by means of open-source algorithms. We validated our findings with external data and obtained results consistent with the previous findings.

Conclusions

Our analysis opens up a new possibility to identify different cell populations from lung samples and promotes sputum induction as a tool to study immune cell populations from the lung.
Discriminative feature of cells characterizes cell populations of interest by a small subset of genes
Authors: Fujii Takeru , Maehara Kazumitsu , Fujita Masatoshi , Ohkawa Yasuyuki
Published: March 2021

Differentially expressed gene-based analysis have faced difficulties associated with the inflation of P-values because of both the large sample size and selection bias introduced by exploratory data analysis in single-cell transcriptomics. Here, we propose the concept of discriminative feature of cells (DFC), implemented by logistic regression with an adaptive LASSO penalty. Adaptive LASSO selects a small subset of genes to discriminate a population of interest. DFC well captured non-independent structure of expression patterns such as cell-type-specific markers, specific composition of gene expression, and subcategories of this cell population. DFC may complement existing methods for interpreting large data sets.
TAPAS: an open-source software package for Translational Neuromodeling and Computational Psychiatry
Authors: Frässle Stefan , Aponte Eduardo A. , Bollmann Saskia , Brodersen Kay H. , Do Cao T. , Harrison Olivia K. , Harrison Samuel J. , Heinzle Jakob , Iglesias Sandra , Kasper Lars , Lomakina Ekaterina I. , Mathys Christoph , Müller-Schrader Matthias , Pereira Inês , Petzschner Frederike H. , Raman Sudhir , Schöbi Dario , Toussaint Birte , Weber Lilian A. , Yao Yu , Stephan Klaas E.
Published: March 2021

Psychiatry faces fundamental challenges with regard to mechanistically guided differential diagnosis, as well as prediction of clinical trajectories and treatment response of individual patients. This has motivated the genesis of two closely intertwined fields: (i) Translational Neuromodeling (TN), which develops “computational assays” for inferring patient-specific disease processes from neuroimaging, electrophysiological, and behavioral data; and (ii) Computational Psychiatry (CP), with the goal of incorporating computational assays into clinical decision making in everyday practice. In order to serve as objective and reliable tools for clinical routine, computational assays require end-to-end pipelines from raw data (input) to clinically useful information (output). While these are yet to be established in clinical practice, individual components of this general end-to-end pipeline are being developed and made openly available for community use.

In this paper, we present theTranslationalAlgorithms forPsychiatry-AdvancingScience (TAPAS) software package, an open-source collection of building blocks for computational assays in psychiatry. Collectively, the tools in TAPAS presently cover several important aspects of the desired end-to-end pipeline, including: (i) tailored experimental designs and optimization of measurement strategy prior to data acquisition, (ii) quality control during data acquisition, and (iii) artifact correction, statistical inference, and clinical application after data acquisition. Here, we review the different tools within TAPAS and illustrate how these may help provide a deeper understanding of neural and cognitive mechanisms of disease, with the ultimate goal of establishing automatized pipelines for predictions about individual patients. We hope that the openly available tools in TAPAS will contribute to the further development of TN/CP and facilitate the translation of advances in computational neuroscience into clinically relevant computational assays.
Immunoprofiling reveals novel mast cell receptors and a continuous nature of human lung mast cell heterogeneity
Authors: Rönnberg Elin , Boey Daryl Zhong Hao , Ravindran Avinash , Säfholm Jesper , Orre Ann-Charlotte , Al-Ameri Mamdoh , Adner Mikael , Dahlén Sven-Erik , Dahlin Joakim S. , Nilsson Gunnar
Published: March 2021

Background

Immunohistochemical analysis of granule-associated proteases have revealed that human lungs mast cells constitute a heterogeneous population of cells, with distinct subpopulations identified. However, a systematic and comprehensive analysis of cell surface markers to study human lung mast cell heterogeneity is yet to be performed.

Methods

Human lung mast cells were obtained from lung lobectomies and the expression of 332 cell surface markers were analyzed using flow cytometry and the LEGENDScreen™kit. Markers that exhibited a high variance were selected for additional analyses to reveal whether they correlated and if discrete mast cell subpopulations were discernable.

Results

We identified expression of 102 surface markers on human lung mast cells. Several markers showed a high continuous variation of expression within the mast cell population. Six of these markers correlated: SUSD2, CD49a, CD326, CD34, CD66 and HLA-DR. The expression of these markers also correlated to the size and granularity of the mast cells. However, no marker produced an expression profile consistent with a bi- or multimodal distribution.

Conclusions

LEGENDScreen analysis identified more than 100 cell surface markers on mast cells, out of which 23 have to our knowledge not previously described on human mast cells. Several of the newly described markers are known to be involved in sensing the microenvironment, and their identification can shed new light on mast cell functions. The exhaustive expression profiling of the 332 surface markers failed to detect distinct mast cell subpopulations. Instead, we demonstrate a continuous nature of human lung mast cell heterogeneity.
Niche specificity, polygeny, and pleiotropy in herbivorous insects
Authors: Hardy Nate B , Forister Matt
Published: March 2021

What causes host-use specificity in herbivorous insects? Population genetic models predict specialization when habitat preference can evolve and there is antagonistic pleiotropy at a performance-affecting locus. But empirically for herbivorous insects, host-use performance is governed by many genetic loci, and antagonistic pleiotropy seems to be rare. Here, we use individual-based quantitative genetic simulation models to investigate the role of pleiotropy in the evolution of sympatric host-use specialization when performance and preference are quantitative traits. We look first at pleiotropies affecting only host-use performance. We find that when the host environment changes slowly the evolution of host-use specialization requires levels of antagonistic pleiotropy much higher than what has been observed in nature. On the other hand, with rapid environmental change or pronounced asymmetries in productivity across host species, the evolution of host-use specialization readily occurs without pleiotropy. When pleiotropies affect preference as well as performance, even with slow environmental change and host species of equal productivity, we observe fluctuations in host-use breadth, with mean specificity increasing with the pervasiveness of antagonistic pleiotropy. So, our simulations show that pleiotropy is not necessary for specialization, although it can be sufficient, provided it is extensive or multifarious.
Associations Between Vocal Emotion Recognition and Socio-emotional Adjustment in Children
Authors: Neves Leonor , Martins Marta , Correia Ana Isabel , Castro São Luís , Lima César F.
Published: March 2021

The human voice is a primary channel for emotional communication. It is often presumed that being able to recognise vocal emotions is important for everyday socio-emotional functioning, but direct empirical evidence for this remains scarce. Here, we examined relationships between vocal emotion recognition and socio-emotional adjustment in children. The sample included 6 to 8-year-old children (N= 141). The emotion tasks required them to categorise five emotions conveyed by nonverbal vocalisations (e.g., laughter, crying) and speech prosody: anger, disgust, fear, happiness, sadness, plus neutrality. Socio-emotional adjustment was independently evaluated by the children’s teachers using a multi-dimensional questionnaire of self-regulation and social behaviour. Based on frequentist and Bayesian analyses, we found that higher emotion recognition in speech prosody related to better general socio-emotional adjustment. This association remained significant even after accounting for the children’s general cognitive ability, age, sex, and parental education in multiple regressions. Follow-up analyses indicated that the advantages were particularly robust for the socio-emotional dimensions prosocial behaviour and cognitive and behavioural self-regulation. For emotion recognition in nonverbal vocalisations, no associations with socio-emotional adjustment were found. Overall, these results support the close link between children’s emotional prosody recognition skills and their everyday social behaviour.
Genomic epidemiology ofMycobacterium bovisinfection in sympatric badger and cattle populations in Northern Ireland
Authors: Akhmetova Assel , Guerrero Jimena , McAdam Paul , Salvador Liliana C.M. , Crispell Joseph , Lavery John , Presho Eleanor , Kao Rowland R. , Biek Roman , Menzies Fraser , Trimble Nigel , Harwood Roland , Pepler P. Theo , Oravcova Katarina , Graham Jordon , Skuce Robin , du Plessis Louis , Thompson Suzan , Wright Lorraine , Byrne Andrew , Allen Adrian R.
Published: March 2021

Background

Bovine tuberculosis (bTB) is a costly, epidemiologically complex, multi-host, endemic disease. Pathogen whole genome sequencing can improve the resolution of epidemiological tracing. We genome sequenced an exceptional data set of 619Mycobacterium bovisisolates from badgers and cattle in a 100km2bTB ‘hotspot’. Historical molecular subtyping data permitted the targeting of an endemic pathogen lineage, whose long-term persistence provided an opportunity to study genome epidemiology in detail. To assess whether badger population genetic structure was associated with the spatial distribution of pathogen genetic diversity, we microsatellite genotyped hair samples from 769 badgers trapped in this area.

Results

Eight lineages ofM. boviswere circulating in the study area, seven of which were likely non-endemic, and imported by animal movement. The endemic lineage exhibited low genetic diversity with an average inter-isolate genetic distance of 7.6 SNPs (s.d. ± 4.0), consistent with contemporary transmission. Bayesian phylogenetic methods determined an evolutionary rate of 0.30 substitutions per genome per year for this lineage, estimating its emergence 40-50 years before present, while Bayesian Skyline analysis identified significant population expansion of the endemic lineage in the 1990s and again in 2011-2012. The phylogeny revealed distinct sub-lineages, all of which contained isolates from both cattle and badger hosts, indicative of the sharing of closely related strains and inter-species transmission. However, the presence of significant badger population genetic structure was not associated with the spatial distribution ofM. bovisgenetic diversity.

Conclusions

Our data provided unparalleled detail on the evolutionary history of an endemicM. bovislineage. Findings are consistent with ongoing interspecies transmission in the study area but suggest that badger intra-species transmission may not be a major driver of persistence in this area. In addition, the data collected permitted the tracking of incursions of novel pathogen lineages into the study area and means to determine if they were involved in disease transmission.
Tree phyllospheres are a habitat for diverse populations of CO-oxidising bacteria
Authors: Palmer Jess L. , Hilton Sally , Picot Emma , Bending Gary D. , Schäfer Hendrik
Published: March 2021

Background

Carbon monoxide (CO) is a naturally occurring and ubiquitous trace gas in the atmosphere. As a product of combustion processes, it can reach concentrations in the mg/m3range in urban areas, contributing to air pollution. Aerobic CO-degrading microorganisms have been identified previously and are thought to remove ~370 Tg of CO in soils and oceans per year. Based on the presence of genes encoding subunits of the enzyme carbon monoxide dehydrogenase in metagenomes, a large fraction of soil bacteria may have the potential for CO degradation. The activity and diversity of CO-degrading microorganisms in above ground habitats such as the phyllosphere has not been addressed, however, and their potential role in global CO cycling remains unknown.

Results

Monitoring of CO-degradation in leaf washes of two common British trees,Ilex aquifoliumandCrataegus monogyna, demonstrated CO uptake in all samples investigated. Leaf washes ofI. aquifoliumhad significantly higher CO oxidation rates than those ofC. monogyna. A diverse range of bacterial taxa were identified as candidate CO-oxidising taxa based on high-throughput sequencing and multivariate statistical analysis of 16S rRNA amplicon data, as well as functional diversity analysis based oncoxL, the gene encoding the large subunit of CO-dehydrogenase. Candidate CO-oxidising taxa included a range of Rhizobiales and Burkholderiales, of which the Burkholderiales OTUs were abundant colonisers of the phyllosphere at the time of sampling, as indicated by 16S rRNA gene sequencing. In addition, an estimated 12.4% of leaf OTUs in samples of this study containedcoxLhomologues, based on their predicted genomes. We also mined data of publicly available phyllosphere metagenomes for genes encoding subunits of CO-dehydrogenase which indicated that, on average, 25% of phyllosphere bacteria contained CO-dehydrogenase gene homologues. A CO-oxidising Phyllobacteriaceae strain was isolated from phyllosphere samples which contains genes encoding both CODH as well as a RuBisCO.

Conclusions

The phyllosphere, a vast microbial habitat, supports diverse and potentially abundant CO-oxidising bacteria. These findings identify tree phyllosphere bacteria as a potential sink for atmospheric CO and highlight the need for a more detailed assessment of phyllosphere microbial communities in the global cycle of CO.
Performance comparison and in-silico harmonisation of commercial platforms for DNA methylome analysis by targeted bisulfite sequencing
Authors: Tanić Miljana , Moghul Ismail , Rodney Simon , Dhami Pawan , Vaikkinen Heli , Ambrose John , Barrett James , Feber Andrew , Beck Stephan
Published: March 2021

DNA methylation is a key epigenetic modification in the regulation of cell fate and differentiation, and its analysis is gaining increasing importance in both basic and clinical research. Targeted Bisulfite Sequencing (TBS) has become the method of choice for the cost-effective, targeted analysis of the human methylome at base-pair resolution. Here we benchmarked five commercially available TBS platforms, including three hybridization capture-based (Agilent, Roche, and Illumina) and two RRBS-based (Diagenode and NuGen), across 16 samples. A subset of these were also compared to whole-genome DNA methylation sequencing with the Illumina and Oxford Nanopore platforms. We assessed performance with respect to workflow complexity, on/off-target performance, coverage, accuracy and reproducibility. We find all platforms able to produce usable data but major differences for some performance criteria, especially in the number and identity of the CpG sites covered, which affects the interoperability of datasets generated on these different platforms. To overcome this limitation, we used imputation and show that it improves the interoperability from an average of 10.35% (0.8M CpG sites) to 97% (7.6M CpG sites). Our study provides cross-validated guidance on which TBS platform to use for different features of the methylome and offers an imputation-based harmonization solution for improved interoperability between platforms, allowing comparative and integrative analysis.
SGI: Automatic clinical subgroup identification in omics datasets
Authors: Buyukozkan Mustafa , Suhre Karsten , Krumsiek Jan
Published: March 2021

The ‘Subgroup Identification’ (SGI) toolbox provides an algorithm to automatically detect clinical subgroups of samples in large-scale omics datasets. It is based on hierarchical clustering trees in combination with a specifically designed association testing and visualization framework that can process an arbitrary number of clinical parameters and outcomes in a systematic fashion. A multi-block extension allows for the simultaneous use of multiple omics datasets on the same samples. In this paper, we describe the functionality of the toolbox and demonstrate an application example on a blood metabolomics dataset with various clinical biochemistry readouts in a type 2 diabetes case-control study.

Availability and implementation

SGI is an open-source package implemented in R. Package source codes and hands-on tutorials are available athttps://github.com/krumsieklab/sgi. The QMdiab metabolomics data is included in the package and can be downloaded fromhttps://doi.org/10.6084/m9.figshare.5904022.
ExiguobacteriumSp. HA2, isolated from the Ilam Mountains of Iran
Authors: Heidari Reza , Akbariqomi Mostafa , Tavoosidana Gholamreza , Rigi Garshasb
Published: March 2021

A motile, Gram-stain-positive, rod-shaped, non-sporing, tolerate up to 5% NaCl, grew at 0–25 °C, designatedExiguobacteriumsp. HA2 was isolated from the soil of the Ilam Mountains of Iran during October 2016. The major isoprenoid quinone is MK-7 and in the smaller amount are MK-6 and MK-8. Polar lipids included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine. Major fatty acids (>10 %) are isoC13:0, isoC15:0and C16:0. The bacterial cell wall peptidoglycan layer was lysine-glycine. The 16S rRNA sequence was analyzed at the phylogenetic levels. Also, A supplemental comparison was made between five other genes includingcsp, gyrB, hsp70, rpoB,andcitC.According to the results of genotypic and phenotypic characteristics, the strain was categorized in the genusExiguobacterium.This bacterium had the closest relation withExiguobacterium undae,and thus was dubbedExiguobacteriumsp. HA2. The different in the Phenotypic, functional characteristics and phylogenetic indicatedExiguobacteriumsp. HA2 can be regarded as representing considered a novel species within the genusExiguobacterium.
Next-generation biocomputing: mimicking artificial neural network with genetic circuits
Authors: Seak Leo Chi U , Lo Owen Lok In , Suen Wade Chun-Wai , Wu Ming-Tsung
Published: March 2021

Artificial neural network (ANN) is nowadays one of the most used and researched computational methods. In the field of biocomputing, however, synthetic biologists are still using logic gate technologies to design genetic circuits. We here propose and computationally validate a novel method to mimic ANN with genetic circuits. We first describe the flow and the mathematical expression of this genetic circuit design and then we providein silicoproof to support the functionality of our method in regression and classification analyses. We believe that thisde novogenetic circuit design method would have wide applications in biotechnology.
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

Twisted 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

Multidrug 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

Disentangling 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

Polyploid 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

Mitochondrial 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

Neural 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

Evolution 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 area

Quantitative 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

Lysosomes 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

Host 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.