nils-herrmann/clean_scirepeval huggingface dataset:
p38α blocks brown adipose tissue thermogenesis through p38δ inhibition
Venue: PLoS biology

Adipose tissue has emerged as an important regulator of whole-body metabolism, and its capacity to dissipate energy in the form of heat has acquired a special relevance in recent years as potential treatment for obesity. In this context, the p38MAPK pathway has arisen as a key player in the thermogenic program because it is required for the activation of brown adipose tissue (BAT) thermogenesis and participates also in the transformation of white adipose tissue (WAT) into BAT-like depot called beige/brite tissue. Here, using mice that are deficient in p38α specifically in adipose tissue (p38αFab-KO), we unexpectedly found that lack of p38α protected against high-fat diet (HFD)-induced obesity. We also showed that p38αFab-KO mice presented higher energy expenditure due to increased BAT thermogenesis. Mechanistically, we found that lack of p38α resulted in the activation of the related protein kinase family member p38δ. Our results showed that p38δ is activated in BAT by cold exposure, and lack of this kinase specifically in adipose tissue (p38δ Fab-KO) resulted in overweight together with reduced energy expenditure and lower body and skin surface temperature in the BAT region. These observations indicate that p38α probably blocks BAT thermogenesis through p38δ inhibition. Consistent with the results obtained in animals, p38α was reduced in visceral and subcutaneous adipose tissue of subjects with obesity and was inversely correlated with body mass index (BMI). Altogether, we have elucidated a mechanism implicated in physiological BAT activation that has potential clinical implications for the treatment of obesity and related diseases such as diabetes.
Drosophila melanogaster establishes a species-specific mutualistic interaction with stable gut-colonizing bacteria
Venue: PLoS biology

Animals live together with diverse bacteria that can impact their biology. In Drosophila melanogaster, gut-associated bacterial communities are relatively simple in composition but also have a strong impact on host development and physiology. It is generally assumed that gut bacteria in D. melanogaster are transient and their constant ingestion with food is required to maintain their presence in the gut. Here, we identify bacterial species from wild-caught D. melanogaster that stably associate with the host independently of continuous inoculation. Moreover, we show that specific Acetobacter wild isolates can proliferate in the gut. We further demonstrate that the interaction between D. melanogaster and the wild isolated Acetobacter thailandicus is mutually beneficial and that the stability of the gut association is key to this mutualism. The stable population in the gut of D. melanogaster allows continuous bacterial spreading into the environment, which is advantageous to the bacterium itself. The bacterial dissemination is in turn advantageous to the host because the next generation of flies develops in the presence of this particularly beneficial bacterium. A. thailandicus leads to a faster host development and higher fertility of emerging adults when compared to other bacteria isolated from wild-caught flies. Furthermore, A. thailandicus is sufficient and advantageous when D. melanogaster develops in axenic or freshly collected figs, respectively. This isolate of A. thailandicus colonizes several genotypes of D. melanogaster but not the closely related D. simulans, indicating that the stable association is host specific. This work establishes a new conceptual model to understand D. melanogaster–gut microbiota interactions in an ecological context; stable interactions can be mutualistic through microbial farming, a common strategy in insects. Moreover, these results develop the use of D. melanogaster as a model to study gut microbiota proliferation and colonization.
A revised understanding of Tribolium morphogenesis further reconciles short and long germ development
Venue: PLoS biology

In Drosophila melanogaster, the germband forms directly on the egg surface and solely consists of embryonic tissue. In contrast, most insect embryos undergo a complicated set of tissue rearrangements to generate a condensed, multilayered germband. The ventral side of the germband is embryonic, while the dorsal side is thought to be an extraembryonic tissue called the amnion. While this tissue organisation has been accepted for decades and has been widely reported in insects, its accuracy has not been directly tested in any species. Using live cell tracking and differential cell labelling in the short germ beetle Tribolium castaneum, I show that most of the cells previously thought to be amnion actually give rise to large parts of the embryo. This process occurs via the dorsal-to-ventral flow of cells and contributes to germband extension (GBE). In addition, I show that true ‘amnion’ cells in Tribolium originate from a small region of the blastoderm. Together, my findings show that development in the short germ embryos of Tribolium and the long germ embryos of Drosophila is more similar than previously proposed. Dorsal-to-ventral cell flow also occurs in Drosophila during GBE, and I argue that the flow is driven by a conserved set of underlying morphogenetic events in both species. Furthermore, the revised Tribolium fate map that I present is far more similar to that of Drosophila than the classic Tribolium fate map. Lastly, my findings show that there is no qualitative difference between the tissue structure of the cellularised blastoderm and the short/intermediate germ germband. As such, the same tissue patterning mechanisms could function continuously throughout the cellularised blastoderm and germband stages, and easily shift between them over evolutionary time.
CellProfiler 3.0: Next-generation image processing for biology
Venue: PLoS biology

CellProfiler has enabled the scientific research community to create flexible, modular image analysis pipelines since its release in 2005. Here, we describe CellProfiler 3.0, a new version of the software supporting both whole-volume and plane-wise analysis of three-dimensional (3D) image stacks, increasingly common in biomedical research. CellProfiler’s infrastructure is greatly improved, and we provide a protocol for cloud-based, large-scale image processing. New plugins enable running pretrained deep learning models on images. Designed by and for biologists, CellProfiler equips researchers with powerful computational tools via a well-documented user interface, empowering biologists in all fields to create quantitative, reproducible image analysis workflows.
Nonmonotonic recruitment of ventromedial prefrontal cortex during remote memory recall
Venue: PLoS biology

Systems-level consolidation refers to the time-dependent reorganisation of memory traces in the neocortex, a process in which the ventromedial prefrontal cortex (vmPFC) has been implicated. Capturing the precise temporal evolution of this crucial process in humans has long proved elusive. Here, we used multivariate methods and a longitudinal functional magnetic resonance imaging (fMRI) design to detect, with high granularity, the extent to which autobiographical memories of different ages were represented in vmPFC and how this changed over time. We observed an unexpected time course of vmPFC recruitment during retrieval, rising and falling around an initial peak of 8–12 months, before reengaging for older 2- and 5-year-old memories. This pattern was replicated in 2 independent sets of memories. Moreover, it was further replicated in a follow-up study 8 months later with the same participants and memories, for which the individual memory representations had undergone their hypothesised strengthening or weakening over time. We conclude that the temporal engagement of vmPFC in memory retrieval seems to be nonmonotonic, revealing a complex relationship between systems-level consolidation and prefrontal cortex recruitment that is unaccounted for by current theories.
Brain–computer interface use is a skill that user and system acquire together
Venue: PLoS biology

A brain–computer interface (BCI) is a computer-based system that acquires, analyzes, and translates brain signals into output commands in real time. Perdikis and colleagues demonstrate superior performance in a Cybathlon BCI race using a system based on “three pillars”: machine learning, user training, and application. These results highlight the fact that BCI use is a learned skill and not simply a matter of “mind reading.”
Strength in numbers: Collaborative science for new experimental model systems
Venue: PLoS biology

Our current understanding of biology is heavily based on a small number of genetically tractable model organisms. Most eukaryotic phyla lack such experimental models, and this limits our ability to explore the molecular mechanisms that ultimately define their biology, ecology, and diversity. In particular, marine protists suffer from a paucity of model organisms despite playing critical roles in global nutrient cycles, food webs, and climate. To address this deficit, an initiative was launched in 2015 to foster the development of ecologically and taxonomically diverse marine protist genetic models. The development of new models faces many barriers, some technical and others institutional, and this often discourages the risky, long-term effort that may be required. To lower these barriers and tackle the complexity of this effort, a highly collaborative community-based approach was taken. Herein, we describe this approach, the advances achieved, and the lessons learned by participants in this novel community-based model for research.
A speed–fidelity trade-off determines the mutation rate and virulence of an RNA virus
Venue: PLoS biology

Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous because they may allow for increased adaptability. This argument has profound implications because it suggests that pathogenesis in many viral infections depends on rare or de novo mutations. Here, we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3DG64S, has a significant replication defect and that wild-type (WT) and 3DG64S populations have similar adaptability in 2 distinct cellular environments. Experimental evolution of 3DG64S under selection for replicative speed led to reversion and compensation of the fidelity phenotype. Mice infected with 3DG64S exhibited delayed morbidity at doses well above the lethal level, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3DG64S growth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast with what has been suggested for many RNA viruses, we find that within-host spread is associated with viral replicative speed and not standing genetic diversity.
Loss of RXFP2 and INSL3 genes in Afrotheria shows that testicular descent is the ancestral condition in placental mammals
Venue: PLoS biology

Descent of testes from a position near the kidneys into the lower abdomen or into the scrotum is an important developmental process that occurs in all placental mammals, with the exception of five afrotherian lineages. Since soft-tissue structures like testes are not preserved in the fossil record and since key parts of the placental mammal phylogeny remain controversial, it has been debated whether testicular descent is the ancestral or derived condition in placental mammals. To resolve this debate, we used genomic data of 71 mammalian species and analyzed the evolution of two key genes (relaxin/insulin-like family peptide receptor 2 [RXFP2] and insulin-like 3 [INSL3]) that induce the development of the gubernaculum, the ligament that is crucial for testicular descent. We show that both RXFP2 and INSL3 are lost or nonfunctional exclusively in four afrotherians (tenrec, cape elephant shrew, cape golden mole, and manatee) that completely lack testicular descent. The presence of remnants of once functional orthologs of both genes in these afrotherian species shows that these gene losses happened after the split from the placental mammal ancestor. These "molecular vestiges" provide strong evidence that testicular descent is the ancestral condition, irrespective of persisting phylogenetic discrepancies. Furthermore, the absence of shared gene-inactivating mutations and our estimates that the loss of RXFP2 happened at different time points strongly suggest that testicular descent was lost independently in Afrotheria. Our results provide a molecular mechanism that explains the loss of testicular descent in afrotherians and, more generally, highlight how molecular vestiges can provide insights into the evolution of soft-tissue characters.
Intracellular attenuation of BMP signaling via CKIP-1/Smurf1 is essential during neural crest induction
Venue: PLoS biology

The neural crest is induced at the neural plate border during gastrulation by combined bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Wnt signaling. While intermediate BMP levels are critical for this induction, secreted BMP inhibitors are largely absent from the neural plate border. Here, we propose a morphogen model in which intracellular attenuation of BMP signaling sets the required intermediate levels to maintain neural crest induction. We show that the scaffold protein casein kinase interacting protein 1 (CKIP-1) and ubiquitin ligase Smad ubiquitin regulatory factor 1 (Smurf1) are coexpressed with BMP4 at the chick neural plate border. Knockdown of CKIP-1 during a critical period between gastrulation and neurulation causes neural crest loss. Consistent with specific BMP modulation, CKIP-1 loss suppresses phospho-Smads 1/5/8 (pSmad1/5/8) and BMP reporter output but has no effect on Wnt signaling; Smurf1 overexpression (OE) acts similarly. Epistasis experiments further show that CKIP-1 rescues Smurf1-mediated neural crest loss. The results support a model in which CKIP-1 suppresses Smurf1-mediated degradation of Smads, uncovering an intracellular mechanism for attenuation of BMP signaling to the intermediate levels required for maintenance of neural crest induction.
Condensin ATPase motifs contribute differentially to the maintenance of chromosome morphology and genome stability
Venue: PLoS biology

Effective transfer of genetic information during cell division requires a major reorganization of chromosome structure. This process is triggered by condensin, a conserved pentameric ATPase essential for chromosome condensation. How condensin harnesses the energy of ATP hydrolysis to promote chromatin reorganization is unknown. To address this issue, we performed a genetic screen specifically focused on the ATPase domain of Smc4, a core subunit of condensin. Our screen identified mutational hotspots that impair condensin’s ability to condense chromosomes to various degrees. These mutations have distinct effects on viability, genome stability, and chromosome morphology, revealing unique thresholds for condensin enzymatic activity in the execution of its cellular functions. Biochemical analyses indicate that inactivation of Smc4 ATPase activity can result in cell lethality because it favors a specific configuration of condensin that locks ATP in the enzyme. Together, our results provide critical insights into the mechanism used by condensin to harness the energy of ATP hydrolysis for the compaction of chromatin.
Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth in developing mice
Venue: PLoS biology

Catch-up growth after insults to growing organs is paramount to achieving robust body proportions. In fly larvae, injury to individual tissues is followed by local and systemic compensatory mechanisms that allow the damaged tissue to regain normal proportions with other tissues. In vertebrates, local catch-up growth has been described after transient reduction of bone growth, but the underlying cellular responses are controversial. We developed an approach to study catch-up growth in foetal mice in which mosaic expression of the cell cycle suppressor p21 is induced in the cartilage cells (chondrocytes) that drive long-bone elongation. By specifically targeting p21 expression to left hindlimb chondrocytes, the right limb serves as an internal control. Unexpectedly, left–right limb symmetry remained normal, revealing deployment of compensatory mechanisms. Above a certain threshold of insult, an orchestrated response was triggered involving local enhancement of bone growth and systemic growth reduction that ensured that body proportions were maintained. The local response entailed hyperproliferation of spared left limb chondrocytes that was associated with reduced chondrocyte density. The systemic effect involved impaired placental function and IGF signalling, revealing bone–placenta communication. Therefore, vertebrates, like invertebrates, can mount coordinated local and systemic responses to developmental insults that ensure that normal body proportions are maintained.
Haploid selection, sex ratio bias, and transitions between sex-determining systems
Venue: PLoS biology

Sex determination is remarkably dynamic; many taxa display shifts in the location of sex-determining loci or the evolution of entirely new sex-determining systems. Predominant theories for why we observe such transitions generally conclude that novel sex-determining systems are favoured by selection if they equalise the sex ratio or increase linkage with a locus that experiences different selection in males versus females. We use population genetic models to extend these theories in two ways: (1) We consider the dynamics of loci very tightly linked to the ancestral sex-determining loci, e.g., within the nonrecombining region of the ancestral sex chromosomes. Variation at such loci can favour the spread of new sex-determining systems in which the heterogametic sex changes (XY to ZW or ZW to XY) and the new sex-determining region is less closely linked (or even unlinked) to the locus under selection. (2) We consider selection upon haploid genotypes either during gametic competition (e.g., pollen competition) or meiosis (i.e., nonmendelian segregation), which can cause the zygotic sex ratio to become biased. Haploid selection can drive transitions between sex-determining systems without requiring selection to act differently in diploid males versus females. With haploid selection, we find that transitions between male and female heterogamety can evolve so that linkage with the sex-determining locus is either strengthened or weakened. Furthermore, we find that sex ratio biases may increase or decrease with the spread of new sex chromosomes, which implies that transitions between sex-determining systems cannot be simply predicted by selection to equalise the sex ratio. In fact, under many conditions, we find that transitions in sex determination are favoured equally strongly in cases in which the sex ratio bias increases or decreases. Overall, our models predict that sex determination systems should be highly dynamic, particularly when haploid selection is present, consistent with the evolutionary lability of this trait in many taxa.
Coding of self-motion-induced and self-independent visual motion in the rat dorsomedial striatum
Venue: PLoS biology

Evolutionary development of vision has provided us with the capacity to detect moving objects. Concordant shifts of visual features suggest movements of the observer, whereas discordant changes are more likely to be indicating independently moving objects, such as predators or prey. Such distinction helps us to focus attention, adapt our behavior, and adjust our motor patterns to meet behavioral challenges. However, the neural basis of distinguishing self-induced and self-independent visual motions is not clarified in unrestrained animals yet. In this study, we investigated the presence and origin of motion-related visual information in the striatum of rats, a hub of action selection and procedural memory. We found that while almost half of the neurons in the dorsomedial striatum are sensitive to visual motion congruent with locomotion (and that many of them also code for spatial location), only a small subset of them are composed of fast-firing interneurons that could also perceive self-independent visual stimuli. These latter cells receive their visual input at least partially from the secondary visual cortex (V2). This differential visual sensitivity may be an important support in adjusting behavior to salient environmental events. It emphasizes the importance of investigating visual motion perception in unrestrained animals.
Visual attention is not deployed at the endpoint of averaging saccades
Venue: PLoS biology

The premotor theory of attention postulates that spatial attention arises from the activation of saccade areas and that the deployment of attention is the consequence of motor programming. Yet attentional and oculomotor processes have been shown to be dissociable at the neuronal level in covert attention tasks. To investigate a potential dissociation at the behavioral level, we instructed human participants to move their eyes (saccade) towards 1 of 2 nearby, competing saccade targets. The spatial distribution of visual attention was determined using oriented visual stimuli presented either at the target locations, between them, or at several other equidistant locations. Results demonstrate that accurate saccades towards one of the targets were associated with presaccadic enhancement of visual sensitivity at the respective saccade endpoint compared to the nonsaccaded target location. In contrast, averaging saccades, landing between the 2 targets, were not associated with attentional facilitation at the saccade endpoint. Rather, attention before averaging saccades was equally deployed at the 2 target locations. Taken together, our results reveal that visual attention is not obligatorily coupled to the endpoint of a subsequent saccade. Rather, our results suggest that the oculomotor program depends on the state of attentional selection before saccade onset and that saccade averaging arises from unresolved attentional selection.