bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial Pyruvate Carrier Inhibition Initiates Metabolic Crosstalk to Stimulate Branched Chain Amino Acid Catabolism
Authors: Ferguson Daniel , Eichler Sophie J. , Yiew Nicole K.H. , Colca Jerry R. , Cho Kevin , Patti Gary J. , Lutkewitte Andrew J. , McCommis Kyle S. , Niemi Natalie M. , Finck Brian N.
Published: May 2022

Objective

The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH.

Methods

Circulating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE;NCT02784444). In this 52-week trial, patients were randomly assigned to placebo (n = 94) or 250 mg MSDC-0602K (n = 101). Human hepatoma cell lines were used to test the direct effects of various MPCi on BCAA catabolism in vitro. Lastly, we investigated how hepatocyte-specific deletion of MPC2 affects BCAA catabolism in the liver of obese mice.

Results

In patients with NASH, MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH), which is deactivated by phosphorylation. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism; an effect that required the BCKDH phosphatase PPM1K. Mechanistically, the effects of MPCi were linked to activation of the energy sensing AMP-dependent protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) kinase signaling cascades. Finally, BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2-/-) mice compared to wild-type controls concomitant with activation of mTOR signaling in vivo.

Conclusions

These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation by activating the AMPK/mTOR axis.
The homodimeric structure of the LARGE1 dual glycosyltransferase
Authors: Katz Michael , Diskin Ron
Published: May 2022

LARGE1 is a bifunctional glycosyltransferase responsible for generating a long linear polysaccharide termed matriglycan that links the cytoskeleton and the extracellular matrix and is required for proper muscle function. This matriglycan polymer is made with an alternating pattern of xylose and glucuronic acid monomers. Mutations in the LARGE1 gene have been shown to cause life-threatening dystroglycanopathies through the inhibition of matriglycan synthesis. Despite its major role in muscle maintenance, the structure of the LARGE1 enzyme and how it assembles in the Golgi are unknown. Here we present the structure of LARGE1, obtained by a combination of X-ray crystallography and single-particle cryo-EM. We found that LARGE1 homo-dimerizes in a configuration that is dictated by its coiled-coil stem domain. The structure shows that this enzyme has two canonical GT-A folds with each of its catalytic domains. In the context of its dimeric structure, the two types of catalytic domains are brought into close proximity from opposing monomers to allow efficient shuttling of the substrate between the two domains. Together with putative retention of matriglycan by electrostatic interactions, this dimeric organization offers a possible mechanism for the high processivity of LARGE1. The structural information further reveals the mechanisms in which disease-causing mutations disrupt the activity of LARGE1. Collectively, these data shed light on how matriglycan is synthesized alongside the functional significance of glycosyltransferase oligomerization.
Effect on the conformations of spike protein of SARS-CoV-2 due to mutation
Authors: Gupta Aayatti Mallick , Chakrabarti Jaydeb
Published: May 2022

The spike protein of SARS CoV-2 mediates receptor binding and cell entry and is the key immunogenic target for virus neutralization and the present attention of many vaccine layouts. It exhibits significant conformational flexibility. We study the structural fluctuations of spike protein among the most common mutations appeared in variant of concerns (VOC). We report the thermodynamics of conformational changes in mutant spike protein with respect to the wildtype from the distributions of the dihedral angles obtained from the equilibrium configurations generated via all-atom molecular dynamics simulations. We find that the mutation causes the increase in distance between N-terminal domain and receptor binding domain leading to an obtuse angle cosine θ distribution in the trimeric structure in spike protein. Thus, increase in open-state is conferred to the more infectious variants of SARS-CoV-2. The thermodynamically destabilized and disordered residues of receptor binding motif among the mutant variants of spike protein are proposed to serve as better binding sites for host factor. We identify a short stretch of region connecting the N-terminal domain and receptor binding domain forming linker loop where many residues undergo stabilization in the open state compared to the closed one.
Ena/VASP clustering at microspike tips involves Lamellipodin but not I-BAR proteins, and absolutely requires unconventional Myosin-X
Authors: Pokrant Thomas , Hein Jens Ingo , Körber Sarah , Disanza Andrea , Pich Andreas , Scita Giorgio , Rottner Klemens , Faix Jan
Published: May 2022

Sheet-like membrane protrusions at the leading edge, termed lamellipodia, drive 2D-cell migration using active actin polymerization. Microspikes comprise actin-filament bundles embedded within lamellipodia, but the molecular mechanisms driving their formation and their potential functional relevance have remained elusive. Microspike formation requires the specific activity of clustered Ena/VASP proteins at their tips to enable processive actin assembly in the presence of capping protein, but the factors and mechanisms mediating Ena/VASP clustering are poorly understood. Systematic analyses of B16-F1 melanoma mutants lacking potential candidate proteins revealed that neither inverse BAR-domain proteins, nor lamellipodin or Abi are essential for clustering, although they differentially contribute to lamellipodial VASP accumulation. In contrast, unconventional myosin-X (MyoX) identified here as proximal to VASP was obligatory for Ena/VASP clustering and microspike formation. Interestingly, and despite the invariable distribution of other relevant marker proteins, the width of lamellipodia in MyoX-KO mutants was significantly reduced as compared to B16-F1 control, suggesting that microspikes contribute to lamellipodium stability. Consistently, MyoX removal caused marked defects in protrusion and random 2D-cell migration. Strikingly, Ena/VASP-deficiency also uncoupled MyoX cluster dynamics from actin assembly in lamellipodia, establishing their tight functional association in microspike formation.

Significance Statement

Unlike filopodia that protrude well beyond the cell periphery and are implicated in sensing, morphogenesis and cell-to-cell communication, the function of microspikes consisting of actin-filament bundles fully embedded within lamellipodia is less clear. Microspike formation involves specific clustering of Ena/VASP family members at filament-barbed ends to enable processive actin polymerization in the presence of capping protein, but the factors and mechanisms mediating Ena/VASP clustering have remained unknown. Here, we systematically analyzed these processes in genetic knockout mutants derived from B16-F1 cells and show that Ena/VASP clustering at microspike tips involves Lamellipodin, but not inverse BAR-domain proteins, and strictly requires unconventional Myosin-X. Complete loss of microspikes was confirmed with CRISPR/Cas9-mediated MyoX knockout in Rat2 fibroblasts, excluding cell type-specific effects.
Genome-wide selection inference at short tandem repeats
Authors: Huang Bonnie , Durvasula Arun , Mousavi Nima , Ziaei-Jam Helyaneh , Maksimov Mikhail , Lohmueller Kirk E. , Gymrek Melissa
Published: May 2022

Short tandem repeats (STRs) comprising repeated sequences of 1-6 bp are one of the largest sources of genetic variation in humans. STRs are known to contribute to a variety of disorders, including Mendelian diseases, complex traits, and cancer. Based on their functional importance, mutations at some STRs are likely to introduce negative effects on reproductive fitness over evolutionary time. We previously developed SISTR (Selection Inference at STRs), a population genetics framework to measure negative selection against individual STR alleles. Here, we extend SISTR to enable joint estimation of the distribution of selection coefficients across a set of STRs. This method (SISTR2) allows for more accurate analysis of a broader range of STRs, including loci with low mutation rates. We apply SISTR2 to explore the range of feasible mutation parameters and demonstrate substantial variation in mutation and selection parameters across different classes of STRs. Finally, we show that de novo STR mutations tend to confer a greater selective burden compared to standing STR variation in the population and measure the relative burden of STRs vs. single nucleotide variants in a typical genome. Overall, we anticipate that the evolutionary insights gained from this study will be important for future studies of variation at STRs and their role in evolution and disease.
A machine learning approach for automatic sleep staging using heart rate variability
Authors: Chakraborty Suvradeep , Goyal Manish , Goyal Paritosh , Mishra Priyadarshini
Published: May 2022

This manuscript has been withdrawn by bioRxiv as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Photoperiod and vernalization alleles and their combinations greatly affected phenological and agronomic traits in bread wheat under autumn and spring sowing conditions
Authors: Amo Aduragbemi , Serikbay Dauren , Song Luxing , Chen Liang , Hu Yin-Gang
Published: May 2022

The responses to temperature (vernalization) and day length (photoperiod) in wheat (Triticum aestivum L.) are entirely defined by allelic differences at the respective VRN-1 and PPD-1 loci. These two physiological factor greatly affect wheat phenology. Using molecular markers, a panel of 61 diverse bread wheat varieties were genotyped for VRN-1 and PPD-1 alleles, and the traits were evaluated under autumn and spring sowing conditions to investigate the impact of the alleles and their combinations on phenological stage, morphological traits, and yield traits. The results revealed that the earlier heading (HD), and flowering (FD) conferred by insensitive alleles for VRN-1 and PPD-1 genes was consistent regardless of the variation under the two sowing conditions. The effects of a single dominant allele of VRN-1 were similar, with an additive effects when combined. The effects of a single PPD-1 insensitive allele differed, with Ppd-D1a stronger than Ppd-B1a, and Ppd-A1a was the least, with an additive effects when combined. Secondly, varieties sown under spring condition recorded a larger flag leaf area when compared to those sown under autumn condition regardless of the single and combined influence at the VRN-1 and PPD-1 loci. When compared to other genes, PPD-D1 had a consistent and significant effect on flag leaf area, spike length, and plant height across both sowing conditions. Furthermore, the sensitive allele Ppd-D1b had larger biomass across both sowing conditions, but this did not translate into increased yield because the Ppd-D1a insensitive allele recorded higher yield. The impact of PPD-D1 gene on grain yield was evident across both sowing conditions. Overall, according to the findings of this study, VRN-1 and PPD-1 genes impact in modulating phenology stages, morphological, spike and yield traits was dependent on the sowing conditions and also on genetic background with the spring and insensitive alleles poised to be favored for selection.
Environmental selection, rather than neutral processes, best explain patterns of diversity in a tropical rainforest fish
Authors: Gates Katie , Sandoval-Castillo Jonathan , Brauer Chris J. , Unmack Peter J. , Laporte Martin , Bernatchez Louis , Beheregaray Luciano B.
Published: May 2022

To conserve the high functional and genetic variation in hotspots such as tropical rainforests, it is essential to understand the forces driving and maintaining biodiversity. We asked to what extent environmental gradients and terrain structure affect morphological and genomic variation across the wet tropical distribution of an Australian rainbowfish, Melanotaenia splendida splendida. We used an integrative riverscape genomics and morphometrics framework to assess the influence of these factors on both putative adaptive and non-adaptive spatial divergence. We found that neutral genetic population structure was largely explainable by restricted gene flow among drainages. However, environmental associations revealed that ecological variables had a similar power to explain overall genetic variation, and greater power to explain body shape variation, than the included neutral covariables. Hydrological and thermal variables were the best environmental predictors and were correlated with traits previously linked to heritable habitat-associated dimorphism in rainbowfishes. Additionally, climate-associated genetic variation was significantly associated with morphology, supporting heritability of shape variation. These results support the inference of evolved functional differences among localities, and the importance of hydroclimate in early stages of diversification. We expect that substantial evolutionary responses will be required in tropical rainforest endemics to mitigate local fitness losses due to changing climates.
Detection of Borrelia garinii in the USA
Authors: Rudenko Natalie , Golovchenko Maryna , Horak Ales , Grubhoffer Libor , Mongodin Emmanuel F. , Fraser Claire M. , Qiu Weigang , Luft Benjamin J. , Morgan Richard G. , Casjens Sherwood R. , Schutzer Steven E.
Published: May 2022

Borrelia garinii, is a cause of Lyme disease in Europe and Asia. For the first time, we report it in the southeastern United States in rodents. Whole genome sequencing and phylogenetic analysis revealed that USA-located B. garinii is part of a clade consisting primarily of few European and majority of Far Eastern strains. Continued surveillance of wildlife hosts and ticks is necessary to assess the ecological status and public health risks of B. garinii in southeastern US.
Ecological Drivers of Community Cohesion
Authors: Gokhale Chaitanya S. , Velasque Mariana , Denton Jai A.
Published: May 2022

From protocellular to societal, networks of living systems are complex and multi-scale. The assembly of these intricate interdependencies, under ecological pressures, can be nearly impossible to understand using pairwise methods. We develop a mathematical and computational model based on a four-strain Saccharomyces cerevisiae synthetic inter-dependent system. Our system leverages transiently structured ecologies for achieving community cohesion. We show how ecological interventions could reverse or slow the extinction rate of a cohesive community. An interconnected system first needs to persist long enough to be a subject of natural selection. Our emulation of Darwin’s warm little ponds’ with an ecology governed by transient compartmentalisation provides the necessary persistence. Our results find utility across scales of organisation, stressing the importance of cyclic processes in major evolutionary transitions engineering of synthetic microbial consortia and conservation biology.
3D Chromatin Structure in Chondrocytes Identifies Putative Osteoarthritis Risk Genes
Authors: Thulson Eliza , Davis Eric S. , D’Costa Susan , Coryell Philip R. , Kramer Nicole E. , Mohlke Karen L. , Loeser Richard F. , Diekman Brian O. , Phanstiel Douglas H.
Published: May 2022

Genome-wide association studies (GWAS) have identified over 100 loci associated with osteoarthrtis (OA) risk, but the majority of OA risk variants are non-coding, making it difficult to identify the impacted genes for further study and therapeutic development. To address this need, we used a multi-omic approach and genome editing to identify and functionally characterize potential OA risk genes. Computational analysis of GWAS and ChIP-seq data revealed that chondrocyte regulatory loci are enriched for OA risk variants. We constructed a chondrocyte specific regulatory network by mapping 3D chromatin structure and active enhancers in human chondrocytes. We then intersected these data with our previously collected RNA-seq dataset of chondrocytes responding to fibronectin fragment (FN-f), a known OA trigger. Integration of the three genomic datasets with recently reported OA GWAS variants revealed a refined set of putative causal OA variants and their potential target genes. One of the novel putative target genes identified wasSOCS2, which was connected to a putative causal variant by a 170 Kb loop and is differentially regulated in response to FN-f. CRISPR-Cas9-mediated deletion ofSOCS2in primary human chondrocytes from three independent donors led to heightened expression of inflammatory markers after FN-f treatment. These data suggest thatSOCS2plays a role in resolving inflammation in response to cartilage matrix damage and provides a possible mechanistic explanation for its influence on OA risk. In total, we identified 56 unique putative OA risk genes for further research and potential therapeutic development.
Whole-brain computation of cognitive versus acoustic errors in music
Authors: Bonetti L. , Carlomagno F. , Kliuchko M. , Gold B.P. , Palva S. , Haumann N.T. , Tervaniemi M. , Huotilainen M. , Vuust P. , Brattico E.
Published: May 2022

Previous studies have evidenced how the local prediction of physical stimulus features may affect the neural processing of incoming stimuli. Less known are the effects of cognitive priors on predictive processes, and how the brain computes local versus cognitive predictions and their errors. Here, we determined the differential brain mechanisms underlying prediction errors related to high-level, cognitive priors for melody (rhythm, contour) versus low-level, local acoustic priors (tuning, timbre). We measured with magnetoencephalography the mismatch negativity (MMN) prediction error signal in 104 adults having varying levels of musical expertise. We discovered that the brain regions involved in predictive processes for local priors were primary and secondary auditory cortex and insula, whereas cognitive brain regions such as cingulate and orbitofrontal cortices were recruited for melodic errors in cognitive priors. The involvement of higher-level brain regions for computing cognitive errors was enhanced in musicians, especially in cingulate cortex, inferior frontal gyri, and supplementary motor area. Overall, the findings expand knowledge on whole-brain mechanisms of predictive processing and the related MMN generators, previously mainly confined to the auditory cortex, to a frontal network that strictly depends on the type of priors that are to be computed by the brain.
Genetic diversity varies with species traits and latitude in predatory soil arthropods (Myriapoda: Chilopoda)
Authors: Bharti D. K. , Pawar Pooja Yashwant , Edgecombe Gregory D. , Joshi Jahnavi
Published: May 2022

Aim

To investigate the drivers of intra-specific genetic diversity in centipedes, a group of ancient predatory soil arthropods.

Location

Global

Time period

Present

Major taxa studied

Centipedes (Class: Chilopoda)

Methods

We assembled a database of over 1200 mitochondrial cytochrome c oxidase subunit I sequences representing 120 centipede species from all five orders of Chilopoda. We used this sequence dataset to estimate genetic diversity for centipede species and compared its distribution with estimates from other arthropod groups. We studied the variation in centipede genetic diversity with species traits and biogeography using a beta regression framework, controlling for the effect of shared evolutionary history within a family.

Results

We observed a wide variation in genetic diversity across centipede species (0 to 0.1713), which falls towards the higher end of values among arthropods. Overall, 21.51% of the variation in mitochondrial COI genetic diversity in centipedes was explained by a combination of predictors related to life history and biogeography. Genetic diversity decreased with body size and latitudinal position of sampled localities, was greater in species showing maternal care and increased with geographic distance among conspecifics.

Main conclusions

Centipedes fall towards the higher end of genetic diversity among arthropods, which may be related to their long evolutionary history and low dispersal ability. In centipedes, the negative association of body size with genetic diversity may be mediated by its influence on local abundance or the influence of ecological strategy on long-term population history. Species with maternal care had higher genetic diversity, which goes against our expectations and needs further scrutiny. Hemispheric differences in genetic diversity can be due to historic climatic stability and lower seasonality in the southern hemisphere. Overall, we find that despite the differences in mean genetic diversity among animals, similar processes related to life history strategy and biogeography shape the variation within them.
Myeloid cell evolution uncovered by shrimp immune cell analysis at single-cell resolution
Authors: Yang Peng , Chen Yaohui , Huang Zhiqi , Xia Huidan , Cheng Ling , Wu Hao , Zhang Yueling , Wang Fan
Published: May 2022

How myeloid cells evolved from invertebrate to vertebrate is still a mystery. Here we collected circulating hemocytes from a marine invertebrate-Penaeus vannamei via gradient centrifugation and identified prohemocyte, monocytic hemocyte and granulocyte as three major types of cells in shrimp hemolymph by single-cell mRNA sequencing. Additional pseudotime trajectory analysis revealed that shrimp monocytic hemocytes and granulocytes were differentiated from a common progenitor which was similar with that of human myeloid cells. More interestingly, we identified that MH2, a terminal differentiated monocytic hemocyte, was a macrophage-like phagocytic cell which could engulf fluorescein labelled Vibrio parahaemolyticus and shared nine marker genes including inflammasome components Nlrp3 and Casp1 with human macrophage. After that, we compared our classification with traditional shrimp hemocytes classification and found that hyalinocyte included both prohemocyte and monocytic hemocyte while semi-granulocyte included both monocytic hemocyte and granulocyte. In general, our results redefine shrimp hemocyte classification based on functional marker genes and unveil evolutionary trace of myeloid cells in marine invertebrate.
Physical models for chromosome organization to predict multi-contact statistics
Authors: Harju Janni , Messelink Joris J.B. , Broedersz Chase P.
Published: May 2022

Chromosome organization in both eukaryotes and prokaryotes is highly regulated. Organizing mechanisms, such as loop-extrusion, have been extensively studied using Hi-C methods, which measure pairwise contacts between chromosomal regions. New multi-contact methods additionally measure which chromosomal contacts occur simultaneously. Here, we develop three predictors of baseline multi-contact frequencies given pairwise contact data, corresponding to distinct physical limits, and argue that a comparison between data and prediction can lead to biological insight. We test these predictors for two simulated polymer models with cross-linking or loop-extrusion, and find that simulated three-point contacts are only predicted by the physically appropriate approximation. Finally, we apply our approach to previously published experimental multi-contact data from human chromosomes. Strikingly, we discover that observed three-point contact frequencies are well predicted by a formula based on loop-extrusion, suggesting that multi-contact data can give insight into chromosome organization mechanisms.
Stronger sexual dimorphism in fruit flies may be favored when congeners are present and females actively search for mates
Authors: Hippee Alaine C. , Beer Marc A. , Norrbom Allen L. , Forbes Andrew A.
Published: May 2022

Why are some species sexually dimorphic while other closely related species are not? When the degree of sexual dimorphism varies within a genus, an integrative phylogenetic approach may help reveal underlying patterns favoring the evolution of dimorphism. While all female flies in genus Strauzia – a genus of true fruit flies – share a multiply-banded wing pattern, males of four species have patterns wherein bands have “coalesced” into a continuous dark streak across much of the wing. We find that the origin of coalesced male wing patterns and pronounced differences in male wing shape correlate with the presumed origin of host plant sharing in this genus. A survey of North American Tephritidae finds just three other genera with specialist species that share host plants. Each has one or more congeners with wing patterns unusual for that genus, and just one genus, Eutreta, has those unusual wing patterns only in the male sex. Eutreta is also the only other genus among this subset wherein, like Strauzia, males hold territories while females search for mates. Sharing the same hosts may result in reproductive character displacement, and when coupled with a biology wherein females actively search for males, may specifically favor sexually dimorphic wing patterns.
Considerations for Deconvolution: A Case Study with GTEx Coronary Artery Tissues
Authors: Brehm Zachary P. , Sherina Valeriia , Rosenberg Avi Z. , Halushka Marc K. , McCall Matthew N.
Published: May 2022

Differential expression analyses are ubiquitous in the realm of statistical genomics, used to estimate functional differences between genomes of groups of subjects. However, differences in tissue composition between groups may contribute to changes in gene expression, potentially obscuring the detection of functionally significant genes of interest. Deconvolution techniques allow researchers to estimate the abundance of each cell type assumed to be in a tissue. While deconvolution is a useful tool to estimate composition, several crucial considerations must be made when setting up and employing such a workflow in an analysis. We perform a deconvolution on GTEx coronary artery data using CIBERSORT and discuss the challenges and limitations in order to highlight future areas of improvement in the deconvolution framework.
MCell4 with BioNetGen: A Monte Carlo Simulator of Rule-Based Reaction-Diffusion Systems with Python Interface
Authors: Husar Adam , Ordyan Mariam , Garcia Guadalupe C. , Yancey Joel G. , Saglam Ali S. , Faeder James R. , Bartol Thomas M. , Kennedy Mary B. , Sejnowski Terrence J.
Published: May 2022

Biochemical signaling pathways in living cells are often highly organized into spatially segregated volumes, membranes, scaffolds, subcellular compartments, and organelles comprising small numbers of interacting molecules. At this level of granularity stochastic behavior dominates, well-mixed continuum approximations based on concentrations break down and a particle-based approach is more accurate and more efficient. We describe and validate a new version of the open-source MCell simulation program (MCell4), which supports generalized 3D Monte Carlo modeling of diffusion and chemical reaction of discrete molecules and macromolecular complexes in solution, on surfaces representing membranes, and combinations thereof. The main improvements in MCell4 compared to the previous versions, MCell3 and MCell3-R, include a Python interface and native BioNetGen reaction language (BNGL) support. MCell4’s Python interface opens up completely new possibilities for interfacing with external simulators to allow creation of sophisticated event-driven multiscale/multiphysics simulations. The native BNGL support, implemented through a new open-source library libBNG (also introduced in this paper), provides the capability to run a given BNGL model spatially resolved in MCell4 and, with appropriate simplifying assumptions, also in the BioNetGen simulation environment, greatly accelerating and simplifying model validation and comparison.
Between heuristics and optimality: Flexible integration of cost and evidence during information sampling
Authors: Hsiung Abigail , Pearson John M. , Poh Jia-Hou , Hakimi Shabnam , Adcock R. Alison , Huettel Scott A.
Published: May 2022

Effective decision making in an uncertain world requires balancing the benefits of acquiring relevant information with the costs of delaying choice. Optimal strategies for information sampling can be accurate but computationally expensive, whereas heuristic strategies are often computationally simple but rigid. To characterize the computations that underlie information sampling, we examined choice processes in human participants who sampled sequences of images (e.g. indoor and outdoor scenes) and attempted to infer the majority category (e.g. indoor or outdoor) under two reward conditions. We examined how behavior maps onto potential information sampling strategies. We found that choices were best described by a flexible function that lay between optimality and heuristics; integrating the magnitude of evidence favoring each category and the number of samples collected thus far. Integration of these criteria resulted in a trade-off between evidence and samples collected, in which the strength of evidence needed to stop sampling decreased linearly as the number of samples accumulated over the course of a trial. This non-optimal trade-off best accounted for choice behavior even under high reward contexts. Our results demonstrate that unlike the optimal strategy, humans are performing simple accumulations instead of computing expected values, and that unlike a simple heuristic strategy, humans are dynamically integrating multiple sources of information in lieu of using only one source. This evidence-by-costs tradeoff illustrates a computationally efficient strategy that balances competing motivations for accuracy and cost minimization.
A dynamic HIF1α- PPARγ circuit controls a paradoxical adipocyte regulatory landscape
Authors: Kudo Takamasa , Zhao Michael L. , Kovary Kyle , LaGory Edward L. , Covert Markus W. , Teruel Mary N.
Published: May 2022

Hypoxia-induced upregulation of HIF1α triggers adipose tissue dysfunction and insulin resistance in obese patients. HIF1α closely interacts with PPARγ, the master regulator of adipocyte differentiation and lipid accumulation, but there are conflicting results how this co-regulation controls the excessive lipid accumulation that drives adipocyte dysfunction. Using single-cell imaging and modeling, we find that, surprisingly, HIF1α both promotes and represses lipid accumulation during adipogenesis. We show that the opposing roles of HIF1α are isolated from each other and depend on when HIF1α increases relative to the positive-feedback mediated upregulation of PPARγ that drives adipocyte differentiation. A theoretical model incorporating our findings resolves conflicting prior results and suggests that three network nodes before and after the isolation step have to be synergistically targeted in therapeutic strategies to revert hypoxia-mediated adipose tissue dysfunction in obesity.

Teaser

A systems biology approach detangles the effect of hypoxic and adipogenic regulators on lipid accumulation in adipocytes.
Trait-dependent diversification in angiosperms: patterns, models and data
Authors: Helmstetter Andrew J. , Zenil-Ferguson Rosana , Sauquet Hervé , Otto Sarah P. , Méndez Marcos , Vallejo-Marin Mario , Schönenberger Jürg , Burgarella Concetta , Anderson Bruce , de Boer Hugo , Glémin Sylvain , Käfer Jos
Published: May 2022

Variation in species richness across the tree of life, accompanied by the incredible variety of ecological and morphological characteristics found in nature, has inspired many studies to link traits with species diversification. Angiosperms are a highly diverse group that has fundamentally shaped life on earth since the Cretaceous, and illustrate how species diversification affects ecosystem functioning. Numerous traits and processes have been linked to differences in species richness within this group, but we know little about how these interact and their relative importance. Here, we synthesized data from 152 studies that used state-dependent speciation and extinction (SSE) models on angiosperm clades. Intrinsic traits related to reproduction and morphology were often linked to diversification but a set of universal drivers did not emerge as traits did not have consistent effects across clades. Importantly, dataset properties were correlated to SSE model results - trees that were larger, older, or less well-sampled tended to yield trait-dependent outcomes. We compared these properties to recommendations for SSE model use and provide a set of best practices to follow when designing studies and reporting results. Finally, we argue that SSE model inferences should be considered in a larger context incorporating species’ ecology, demography and genetics.
Growth, organic matter release, aggregation and recycling during a diatom bloom: A model-based analysis of a mesocosm experiment
Authors: Kerimoglu Onur , Hintz Nils H. , Lücken Leonhard , Blasius Bernd , Böttcher Lea , Bunse Carina , Dittmar Thorsten , Heyerhoff Benedikt , Mori Corinna , Striebel Maren , Simon Meinhard
Published: May 2022

Mechanisms terminating phytoplankton blooms are often not well understood. Potentially involved processes such as consumption by grazers, flocculation, and viral lysis each have different post-bloom consequences on the processing of the organic material, therefore it is important to develop a better understanding of the relevance of these processes, and potential interactions between them. In this study, we present a model-based analysis of a spring bloom observed in a mesocosm experiment. The intermediate-complexity (27-state variable) numerical model we extended from an earlier version to this end can resolve C, N, P and Si cycles, and relevant processes like formation of various organic material size classes (low and high molecular weight (hereafter small and large) dissolved organic carbon (DOC), transparent exopolymer particles (TEP), and small/large detritus) and their degradation by two bacterial sub-communities (free-living and particle-attached) and planktonic protists (heterotrophic flagellates and ciliates). The model can explain > 90% of the variation of a rich set of observations consisting of 11 independent variables over the course of 13 days during which a bloom largely dominated by diatoms develops, and disappears almost entirely. Fluxes estimated by the model point to the importance of coagulation (TEP formation) as a sink term for DOC, and a source term for POC. Consequently, aggregation with TEPs constitute an important loss term for phytoplankton. The flocculated phytoplankton, and detrital material, in turn become rapidly degraded by the particle attached bacteria and other protist heterotrophs. Through a scenario analysis, the relevance of nutrient-stress enhanced lysis rates; alterations between small and large DOC in phytoplankton exudates; and coagulation of smaller DOC molecules were investigated. Our results suggest that the former two processes have negligible effects in isolation, but when combined with the latter, they can synergistically cause substantial deviations in TEP formation, hence, in flocculation rates; and consequently in the peak magnitude of the diatom bloom, and in timing of its termination. Our results point to a need for better understanding of processes governing the termination of phytoplankton blooms, their inter-dependencies, and consequences on the global biogeochemical cycles.
Analyses of circRNA expression throughout circadian rhythm reveal a strong link between Cdr1as and light-induced phase shifts in the SCN
Authors: Ivanov Andranik , Mattei Daniele , Radscheit Kathrin , Compagnion Anne-Claire , Pett J. Patrick , Herzel Hanspeter , Paolicelli Rosa Chiara , Piwecka Monika , Meyer Urs , Beule Dieter
Published: May 2022

Cdr1as is a conserved circular RNA (circRNA) enriched in the CNS and important for maintaining brain homeostasis. The loss of Cdr1as results in aberrant synaptic transmission and deregulation of stress response and circadian clock genes. However, it is not known whether the expression of Cdr1as or circRNAs, in general, follows a circadian pattern in different tissues. Here, using newly generated and public RNA-Seq data, we monitor circRNA expression throughout circadian rhythm in various mouse brain regions. We demonstrate that Cdr1as, despite its stable character, has a highly dynamic expression during the circadian cycle in the mouse suprachiasmatic nucleus (SCN). Cdr1as is one of the highest expressed RNAs in a cluster associated with light-induced synaptic transmission and phase shift in the SCN. Further, we identified that another brain enriched circRNA, mbl, is also substantially deregulated upon light induction in the fly head. Our study highlights the potential impact of abundant and conserved circRNAs on maintaining a healthy circadian cycle across species.
Carbon signaling protein SbtB possesses redox-regulated apyrase activity to facilitate regulation of bicarbonate transporter SbtA
Authors: Selim Khaled A. , Haffner Michael , Albrecht Reinhard , Zhu Hongbo , Forchhammer Karl , Hartmann Marcus D.
Published: May 2022

The PII superfamily consists of widespread signal transduction proteins found in all domains of life. In addition to canonical PII proteins involved in C/N sensing, structurally similar PII-like proteins evolved to fulfill diverse, yet poorly understood cellular functions. In cyanobacteria, the bicarbonate transporter SbtA is expressed with the conserved PII-like protein, SbtB, to augment intracellular Ci levels for efficient CO2-fixation. We identified SbtB as a sensor of various adenine nucleotides including the second messenger nucleotides cAMP, known as carbon-status indicator, and c-di-AMP, involved in global cellular homeostasis. Moreover, many SbtB proteins possess a C-terminal extension with a disulfide bridge. We previously implied a redox-regulatory function of this extension, which we now call R-loop. Here, we reveal an unusual ATP/ADP apyrase (diphosphohydrolase) activity of SbtB that is controlled by the R-loop. We followed the sequence of the hydrolysis reactions from ATP over ADP to AMP in crystal-lographic snapshots and reveal the structural mechanism by which changes of the R-loop redox state modulate apyrase activity. We further gathered evidence that this redox state is controlled by thioredoxin TrxA, suggesting that it is generally linked to cellular metabolism. Finally, we present a refined model of how SbtB regulates SbtA activity, in which both the apyrase activity and its redox regulation play a central role. This highlights SbtB as a central switch-point in cyanobacterial cell physiology, integrating not only signals from the energy state (adenyl-nucleotide binding) and the carbon supply via cAMP binding, but also from the day/night status reported by the C-terminal redox-switch.
Curvature-induced cell rearrangements in biological tissues
Authors: Lou Yuting , Rupprecht Jean-Francois , Hiraiwa Tetsuya , Saunders Timothy E
Published: May 2022

On a curved surface, epithelial cells can adapt to geometric constraints by tilting and by exchanging their neighbors from apical to basal sides, known as an apicobasal T1 (AB-T1) transition. The relationship between cell tilt, AB-T1 transitions, and tissue curvature still lacks a unified understanding. Here, we propose a general framework for cell packing in curved environments and explain the formation of AB-T1 transitions under different conditions. We find that steep curvature gradients can lead to cell tilting and induce AB-T1 transitions. Conversely, large curvature anisotropy can drive AB-T1 transitions by hydrostatic pressure. The two mechanisms compete to determine the impact of tissue geometry and mechanics on optimized cell rearrangements in 3D.
SARS-CoV-2 Subunit Virus-Like Vaccine Demonstrates High Safety Profile and Protective Efficacy: Preclinical Study
Authors: Vakhrusheva A.V. , Kudriavtsev A.V. , Kryuchkov N.A. , Deev R.V. , Frolova M.E. , Blagodatskikh K.A. , Djonovic M. , Nedorubov A.A. , Odintsova E. , Ivanov A.V. , Romanovskaya-Romanko E.A. , Stukova M.A. , Isaev A.A. , Krasilnikov I.V.
Published: May 2022

Public health threat coming from a rapidly developing COVID-19 pandemic calls for developing safe and effective vaccines with innovative designs. This paper presents preclinical trial results of “Betuvax-CoV-2”, a vaccine developed as a subunit vaccine containing a recombinant RBD-Fc fusion protein and betulin-based spherical virus-like nanoparticles as an adjuvant (“Betuspheres”). The aim of the study was to demonstrate vaccine safety in mice, rats, and Chinchilla rabbits through acute, subchronic, and reproductive toxicity studies. Along with safety, the vaccine demonstrated protective efficacy through SARS-CoV-2-neutralizing antibody production in mice, rats, hamsters, rabbits, and primates (rhesus macaque), and lung damage and infection protection in hamsters and rhesus macaque model. Eventually, “Betuvax-CoV-2” was proved to confer superior efficacy and protection against the SARS-CoV-2 in preclinical studies. Based on the above results, the vaccine was enabled to enter clinical trials that are currently underway.
Chromosome folding and prophage activation reveal gut-specific genome dynamics of bacteria in the OMM12consortium
Authors: Lamy-Besnier Quentin , Bignaud Amaury , Garneau Julian R. , Titecat Marie , Conti Devon , Von Strempel Alexandra , Monot Marc , Stecher Bärbel , Koszul Romain , Debarbieux Laurent , Marbouty Martial
Published: May 2022

Bacteria and their viruses, bacteriophages, are the most abundant entities of the gut microbiota, a complex community of microorganisms associated with human health and disease. In this ecosystem the interactions between these two key components are still largely unknown. In particular, the impact of the gut environment on bacteria and their associated prophages is yet to be deciphered. To gain insight into the activity of lysogenic phages within the context of their host genomes, we performed Hi-C on the 12 strains of the OMM12synthetic bacterial community stably associated within mice gut (gnotobiotic mouse line OMM12) in bothin vitroandin vivoconditions. High-resolution contact maps of the chromosome 3D organization of the bacterial genomes revealed a wide diversity of architectures, differences between environments and an overall stability over time in the gut of mice. The DNA contacts also pointed at 3D signatures of prophages leading to predict 16 of them as functional. We identified circularization signals and observed different 3D patterns depending on the condition. Concurrent virome analysis showed that 11 of these prophages produced viral particlesin vivoand/orin vitro, and that OMM12mice do not carry other intestinal viruses. By predicting functional prophages, the Hi-C approach unlocks the study of phage-bacteria interaction dynamics.
Cross regulation between the molecular clock and kidney inflammatory, metabolic and fibrotic responses
Authors: Rey-Serra Carlos , Tituaña Jessica , Lin Terry , Herrero J. Ignacio , Miguel Verónica , Barbas Coral , Meseguer Anna , Ramos Ricardo , Firsov Dmitri , Chaix Amandine , Panda Satchidananda , Lamas Santiago
Published: May 2022

Chronic kidney disease is a highly prevalent condition that remains a major clinical and biomedical challenge. Tubulo-interstitial fibrosis is the common pathological substrate for many causes that lead to chronic kidney disease. It is characterized by profound derangements in metabolic and inflammatory responses, whereby functional tissue is replaced with extracellular matrix, leading to the suppression of renal function. Perturbations in the circadian rhythm have been associated with many human pathologies, including renal disease. However, the role of the molecular clock in the instauration of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (UUO, FAN and adenine toxicity), employing genetically-modified mice with selective deficiencies of the clock components Bmal1, Clock and Cry. We found that UUO induced a marked increase in the expression of Bmal1. In human tubular epithelial cells, the pro-fibrotic mediator, TGF-β, significantly altered the expression of core clock components. We further observed that the absence of Cry drastically aggravated kidney fibrosis, while both Cry and Clock played a role in the neutrophil and macrophage mediated inflammatory response, respectively. Suppression of Cry1/2 was associated with a major shift in the expression of metabolism-related genes, underscoring the importance of metabolic dysfunction in fibrosis. These results support a reciprocal interaction between the circadian clock and the response to kidney injury.

Translational statement

Chronic kidney disease (CKD) is a highly prevalent clinical syndrome that still poses major clinical challenges. Kidney fibrosis underlies many cases of CKD and therapies against it are of very limited efficacy. Alterations in circadian rhythms (CR) are relevant in patients with CKD, but very little is known about the relationship between CKD and CR. Our study shows that disruption of the molecular clock can impact kidney inflammation and fibrosis and that, reciprocally, kidney fibrosis can alter the expression of clock components. A better understanding of this crosstalk could open new therapeutic avenues for the prevention and treatment of CR-related CKD.
Zmiz1 is required for mature β-cell function and mass expansion upon high fat feeding
Authors: Alghamdi Tamadher A. , Krentz Nicole A. J. , Smith Nancy , Spigelman Aliya F. , Rajesh Varsha , Jha Alok , Ferdaoussi Mourad , Manning Fox Jocelyn E , Sun Han , Sun Zijie , Gloyn Anna L. , MacDonald Patrick E.
Published: May 2022

Genome-wide association studies have identified hundreds of signals for type 2 diabetes (T2D), most of which confer risk through effects on gene expression. We previously identified the transcription factor ZMIZ1 as a probable effector transcript in human islets, but how altered ZMIZ1 expression impacts T2D risk is unknown. We now show that islets from carriers of the T2D-risk alleles have reduced islet insulin content and glucose-stimulated insulin secretion. To elucidate the mechanism for islet-cell dysfunction, we generated β-cell-specific Zmiz1 knockout (Zmiz1βKO) mice. Male and female Zmiz1βKO mice were glucose intolerant with impaired insulin secretion, compared with control littermates. Transcriptomic profiling of Zmiz1βKO islets identified over 500 differentially expressed genes including those involved in β-cell function and maturity which we confirmed at the protein level. After high fat feeding, Zmiz1βKO mice fail to expand β-cell mass and become severely diabetic. Thus, Zmiz1 is required for normal glucose homeostasis and may contribute to T2D risk by maintaining a mature β-cell state and allowing islet mass expansion upon metabolic stress.