nils-herrmann/clean_scirepeval huggingface dataset:
Fast calcium transients in dendritic spines driven by extreme statistics
Venue: PLoS biology

Fast calcium transients (<10 ms) remain difficult to analyse in cellular microdomains, yet they can modulate key cellular events such as trafficking, local ATP production by endoplasmic reticulum-mitochondria complex (ER-mitochondria complex), or spontaneous activity in astrocytes. In dendritic spines receiving synaptic inputs, we show here that in the presence of a spine apparatus (SA), which is an extension of the smooth ER, a calcium-induced calcium release (CICR) is triggered at the base of the spine by the fastest calcium ions arriving at a Ryanodyne receptor (RyR). The mechanism relies on the asymmetric distributions of RyRs and sarco/ER calcium-ATPase (SERCA) pumps that we predict using a computational model and further confirm experimentally in culture and slice hippocampal neurons. The present mechanism for which the statistics of the fastest particles arriving at a small target, followed by an amplification, is likely to be generic in molecular transduction across cellular microcompartments, such as thin neuronal processes, astrocytes, endfeets, or protrusions.
Evolution or revolution? Changing the way science is published and communicated
Venue: PLoS biology

The Internet is rapidly changing the way the results of academic research are communicated within communities and with the wider public. In a push to accelerate change and make the results of research immediately and freely available online for all to read and use, the European Commission, with support from a group of high-profile funders, has proposed a plan to influence the way academic research is published. Here, we discuss the likely impact of this plan on the publishing landscape, the potential benefits, and some possible unintended consequences.
Rhythm and time in the premotor cortex
Venue: PLoS biology

Many animals can encode temporal intervals and use them to plan their actions, but only humans can flexibly extract a regular beat from complex patterns, such as musical rhythms. Beat-based timing is hypothesized to rely on the integration of sensory information with temporal information encoded in motor regions such as the medial premotor cortex (MPC), but how beat-based timing might be encoded in neuronal populations is mostly unknown. Gámez and colleagues show that the MPC encodes temporal information via a population code visible as circular trajectories in state space; these patterns may represent precursors to more-complex skills such as beat-based timing.
Plant health emergencies demand open science: Tackling a cereal killer on the run
Venue: PLoS biology

Outbreaks of emerging plant diseases and insect pests are increasing at an alarming rate threatening the food security needs of a booming world population. The role of plant pathologists in addressing these threats to plant health is critical. Here, we share our personal experience with the appearance in Bangladesh of a destructive new fungal disease called wheat blast and stress the importance of open-science platforms and crowdsourced community responses in tackling emerging plant diseases. Benefits of the open-science approach include recruitment of multidisciplinary experts, application of cutting-edge methods, and timely replication of data analyses to increase the robustness of the findings. Based on our experiences, we provide some general recommendations and practical guidance for responding to emerging plant diseases.
Hidden genomic evolution in a morphospecies—The landscape of rapidly evolving genes in Tetrahymena
Venue: PLoS biology

A morphospecies is defined as a taxonomic species based wholly on morphology, but often morphospecies consist of clusters of cryptic species that can be identified genetically or molecularly. The nature of the evolutionary novelty that accompanies speciation in a morphospecies is an intriguing question. Morphospecies are particularly common among ciliates, a group of unicellular eukaryotes that separates 2 kinds of nuclei—the silenced germline nucleus (micronucleus [MIC]) and the actively expressed somatic nucleus (macronucleus [MAC])—within a common cytoplasm. Because of their very similar morphologies, members of the Tetrahymena genus are considered a morphospecies. We explored the hidden genomic evolution within this genus by performing a comprehensive comparative analysis of the somatic genomes of 10 species and the germline genomes of 2 species of Tetrahymena. These species show high genetic divergence; phylogenomic analysis suggests that the genus originated about 300 million years ago (Mya). Seven universal protein domains are preferentially included among the species-specific (i.e., the youngest) Tetrahymena genes. In particular, leucine-rich repeat (LRR) genes make the largest contribution to the high level of genome divergence of the 10 species. LRR genes can be sorted into 3 different age groups. Parallel evolutionary trajectories have independently occurred among LRR genes in the different Tetrahymena species. Thousands of young LRR genes contain tandem arrays of exactly 90-bp exons. The introns separating these exons show a unique, extreme phase 2 bias, suggesting a clonal origin and successive expansions of 90-bp–exon LRR genes. Identifying LRR gene age groups allowed us to document a Tetrahymena intron length cycle. The youngest 90-bp exon LRR genes in T. thermophila are concentrated in pericentromeric and subtelomeric regions of the 5 micronuclear chromosomes, suggesting that these regions act as genome innovation centers. Copies of a Tetrahymena Long interspersed element (LINE)-like retrotransposon are very frequently found physically adjacent to 90-bp exon/intron repeat units of the youngest LRR genes. We propose that Tetrahymena species have used a massive exon-shuffling mechanism, involving unequal crossing over possibly in concert with retrotransposition, to create the unique 90-bp exon array LRR genes.
Representation of abstract semantic knowledge in populations of human single neurons in the medial temporal lobe
Venue: PLoS biology

Sensory experience elicits complex activity patterns throughout the neocortex. Projections from the neocortex converge onto the medial temporal lobe (MTL), in which distributed neocortical firing patterns are distilled into sparse representations. The precise nature of these neuronal representations is still unknown. Here, we show that population activity patterns in the MTL are governed by high levels of semantic abstraction. We recorded human single-unit activity in the MTL (4,917 units, 25 patients) while subjects viewed 100 images grouped into 10 semantic categories of 10 exemplars each. High levels of semantic abstraction were indicated by representational similarity analyses (RSAs) of patterns elicited by individual stimuli. Moreover, pattern classifiers trained to decode semantic categories generalised successfully to unseen exemplars, and classifiers trained to decode exemplar identity more often confused exemplars of the same versus different categories. Semantic abstraction and generalisation may thus be key to efficiently distill the essence of an experience into sparse representations in the human MTL. Although semantic abstraction is efficient and may facilitate generalisation of knowledge to novel situations, it comes at the cost of a loss of detail and may be central to the generation of false memories.
Proteome-wide analysis of chaperone-mediated autophagy targeting motifs
Venue: PLoS biology

Chaperone-mediated autophagy (CMA) contributes to the lysosomal degradation of a selective subset of proteins. Selectivity lies in the chaperone heat shock cognate 71 kDa protein (HSC70) recognizing a pentapeptide motif (KFERQ-like motif) in the protein sequence essential for subsequent targeting and degradation of CMA substrates in lysosomes. Interest in CMA is growing due to its recently identified regulatory roles in metabolism, differentiation, cell cycle, and its malfunctioning in aging and conditions such as cancer, neurodegeneration, or diabetes. Identification of the subset of the proteome amenable to CMA degradation could further expand our understanding of the pathophysiological relevance of this form of autophagy. To that effect, we have performed an in silico screen for KFERQ-like motifs across proteomes of several species. We have found that KFERQ-like motifs are more frequently located in solvent-exposed regions of proteins, and that the position of acidic and hydrophobic residues in the motif plays the most important role in motif construction. Cross-species comparison of proteomes revealed higher motif conservation in CMA-proficient species. The tools developed in this work have also allowed us to analyze the enrichment of motif-containing proteins in biological processes on an unprecedented scale and discover a previously unknown association between the type and combination of KFERQ-like motifs in proteins and their participation in specific biological processes. To facilitate further analysis by the scientific community, we have developed a free web-based resource (KFERQ finder) for direct identification of KFERQ-like motifs in any protein sequence. This resource will contribute to accelerating understanding of the physiological relevance of CMA.
Rapid ultrasensitive detection platform for antimicrobial susceptibility testing
Venue: PLoS biology

Rapid detection and phenotyping of pathogenic microbes is critical for administration of effective antibiotic therapies and for impeding the spread of antibiotic resistance. Here, we present a novel platform, rapid ultrasensitive detector (RUSD), that utilizes the high reflectance coefficient at high incidence angles when light travels from low- to high-refractive-index media. RUSD leverages a principle that does not require complex manufacturing, labeling, or processing steps. Utilizing RUSD, we can detect extremely low cell densities (optical density [OD] ≥ 5 × 10−7) that correspond to approximately 20 bacterial cells or a single fungal cell in the detection volume, which is nearly 4 orders of magnitude more sensitive than standard OD methods. RUSD can measure minimum inhibitory concentrations (MICs) of commonly used antibiotics against gram-negative and gram-positive bacteria, including Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, within 2 to 4 h. Here, we demonstrate that antibiotic susceptibility tests for several pathogens can rapidly be performed with RUSD using both small inoculum sizes (500 cells/mL) and larger inoculum sizes (5 × 105 cells/mL) used in standard antibiotic susceptibility tests. We anticipate that the RUSD system will be particularly useful for the cases in which antibiotic susceptibility tests have to be done with a limited number of bacterial cells that are available. Its compatibility with standard antibiotic susceptibility tests, simplicity, and low cost can make RUSD a viable and rapidly deployed diagnostic tool.
Placental chemokine compartmentalisation: A novel mammalian molecular control mechanism
Venue: PLoS biology

Atypical chemokine receptor 2 (ACKR2) is a chemokine-scavenging receptor. ACKR2–/–embryos display a reduction in size of a novel, to our knowledge, embryonic skin macrophage population referred to as ‘intermediate’ cells. CC chemokine receptor 2 (CCR2)–/–embryos display an identical phenotype, indicating that these cells require CCR2 to enable them to populate embryonic skin. Further analysis revealed that ACKR2–/–embryos have higher circulating concentrations of the CCR2 ligand, CC ligand 2 (CCL2); thus, ACKR2 regulates intraembryonic CCL2 levels. We show that ACKR2 is strongly expressed by trophoblasts and that it blocks movement of inflammatory chemokines, such as CCL2, from the maternal decidua into the embryonic circulation. We propose that trophoblastic ACKR2 is responsible for ensuring chemokine compartmentalisation on the maternal decidua, without which chemokines enter the embryonic circulation, disrupting gradients essential for directed intraembryonic cell migration. Overall, therefore, we describe a novel, to our knowledge, molecular mechanism whereby maternal decidual chemokines can function in a compartmentalised fashion without interfering with intraembryonic leukocyte migration. These data suggest similar functions for other atypical chemokine receptors in the placenta and indicate that defects in such receptors may have unanticipated developmental consequences.
Genotype network intersections promote evolutionary innovation
Venue: PLoS biology

Evolutionary innovations are qualitatively novel traits that emerge through evolution and increase biodiversity. The genetic mechanisms of innovation remain poorly understood. A systems view of innovation requires the analysis of genotype networks—the vast networks of genetic variants that produce the same phenotype. Innovations can occur at the intersection of two different genotype networks. However, the experimental characterization of genotype networks has been hindered by the vast number of genetic variants that need to be functionally analyzed. Here, we use high-throughput sequencing to study the fitness landscape at the intersection of the genotype networks of two catalytic RNA molecules (ribozymes). We determined the ability of numerous neighboring RNA sequences to catalyze two different chemical reactions, and we use these data as a proxy for a genotype to fitness map where two functions come in close proximity. We find extensive functional overlap, and numerous genotypes can catalyze both functions. We demonstrate through evolutionary simulations that these numerous points of intersection facilitate the discovery of a new function. However, the rate of adaptation of the new function depends upon the local ruggedness around the starting location in the genotype network. As a consequence, one direction of adaptation is more rapid than the other. We find that periods of neutral evolution increase rates of adaptation to the new function by allowing populations to spread out in their genotype network. Our study reveals the properties of a fitness landscape where genotype networks intersect and the consequences for evolutionary innovations. Our results suggest that historic innovations in natural systems may have been facilitated by overlapping genotype networks.
Surviving starvation simply without TFEB
Venue: PLoS biology

Starvation is among the most ancient of selection pressures, driving evolution of a robust arsenal of starvation survival defenses. In order to survive starvation stress, organisms must be able to curtail anabolic processes during starvation and judiciously activate catabolic pathways. Although the activation of metabolic defenses in response to nutrient deprivation is an obvious component of starvation survival, less appreciated is the importance of the ability to recover from starvation upon re-exposure to nutrients. In order for organisms to successfully recover from starvation, cells must be kept in a state of ready so that upon the return of nutrients, activities such as growth and reproduction can be resumed. Critical to this state of ready is the lysosome, an organelle that provides essential signals of nutrient sufficiency to cell growth-activating pathways in the fed state. In this issue, Murphy and colleagues provide evidence that exposure of Caenorhabditis elegans roundworms to 2 simple nutrients, glucose and the polyunsaturated fatty acid linoleate, is able to render lysosomal function competent to activate key downstream starvation recovery pathways, bypassing the need for a master transcriptional regulator of lysosomes. These findings provide a quantum leap forward in our understanding of the cellular determinants that permit organisms to survive cycles of feast and famine.
AccessLab: Workshops to broaden access to scientific research
Venue: PLoS biology

AccessLabs are workshops with two simultaneous motivations, achieved through direct citizen-scientist pairings: (1) to decentralise research skills so that a broader range of people are able to access/use scientific research, and (2) to expose science researchers to the difficulties of using their research as an outsider, creating new open access advocates. Five trial AccessLabs have taken place for policy makers, media/journalists, marine sector participants, community groups, and artists. The act of pairing science academics with local community members helps build understanding and trust between groups at a time when this relationship appears to be under increasing threat from different political and economic currents in society. Here, we outline the workshop motivations, format, and evaluation, with the aim that others can build on the methods developed.
Foxp1 is critical for the maintenance of regulatory T-cell homeostasis and suppressive function
Venue: PLoS biology

Regulatory T (Treg) cells play central roles in maintaining immune homeostasis and self-tolerance. However, the molecular mechanisms underlying Treg cell homeostasis and suppressive function are still not fully understood. Here, we report that the deletion of another P subfamily members of the forkhead box (Foxp) subfamily member Foxp1 in Treg cells led to increased numbers of activated Treg (aTreg) cells at the expense of quiescent Treg cells, and also resulted in impaired Treg suppressive function. Mice with Foxp1-deficient Treg cells developed spontaneous inflammatory disease with age; they also had more severe inflammatory disease in colitis and experimental autoimmune encephalomyelitis (EAE) models. Mechanistically, we found that Foxp1 bound to the conserved noncoding sequence 2 (CNS2) element of the Foxp3 locus and helped maintain Treg suppressive function by stabilizing the Foxp3 expression. Furthermore, we found that Foxp1 and Foxp3 coordinated the regulation of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression levels. Taken together, our study demonstrates that Foxp1 plays critical roles in both maintaining Treg cell quiescence during homeostasis and regulating Treg suppressive function.
Cell aging preserves cellular immortality in the presence of lethal levels of damage
Venue: PLoS biology

Cellular aging, a progressive functional decline driven by damage accumulation, often culminates in the mortality of a cell lineage. Certain lineages, however, are able to sustain long-lasting immortality, as prominently exemplified by stem cells. Here, we show that Escherichia coli cell lineages exhibit comparable patterns of mortality and immortality. Through single-cell microscopy and microfluidic techniques, we find that these patterns are explained by the dynamics of damage accumulation and asymmetric partitioning between daughter cells. At low damage accumulation rates, both aging and rejuvenating lineages retain immortality by reaching their respective states of physiological equilibrium. We show that both asymmetry and equilibrium are present in repair mutants lacking certain repair chaperones, suggesting that intact repair capacity is not essential for immortal proliferation. We show that this growth equilibrium, however, is displaced by extrinsic damage in a dosage-dependent response. Moreover, we demonstrate that aging lineages become mortal when damage accumulation rates surpass a threshold, whereas rejuvenating lineages within the same population remain immortal. Thus, the processes of damage accumulation and partitioning through asymmetric cell division are essential in the determination of proliferative mortality and immortality in bacterial populations. This study provides further evidence for the characterization of cellular aging as a general process, affecting prokaryotes and eukaryotes alike and according to similar evolutionary constraints.
Rapamycin directly activates lysosomal mucolipin TRP channels independent of mTOR
Venue: PLoS biology

Rapamycin (Rap) and its derivatives, called rapalogs, are being explored in clinical trials targeting cancer and neurodegeneration. The underlying mechanisms of Rap actions, however, are not well understood. Mechanistic target of rapamycin (mTOR), a lysosome-localized protein kinase that acts as a critical regulator of cellular growth, is believed to mediate most Rap actions. Here, we identified mucolipin 1 (transient receptor potential channel mucolipin 1 [TRPML1], also known as MCOLN1), the principle Ca2+ release channel in the lysosome, as another direct target of Rap. Patch-clamping of isolated lysosomal membranes showed that micromolar concentrations of Rap and some rapalogs activated lysosomal TRPML1 directly and specifically. Pharmacological inhibition or genetic inactivation of mTOR failed to mimic the Rap effect. In vitro binding assays revealed that Rap bound directly to purified TRPML1 proteins with a micromolar affinity. In both healthy and disease human fibroblasts, Rap and rapalogs induced autophagic flux via nuclear translocation of transcription factor EB (TFEB). However, such effects were abolished in TRPML1-deficient cells or by TRPML1 inhibitors. Hence, Rap and rapalogs promote autophagy via a TRPML1-dependent mechanism. Given the demonstrated roles of TRPML1 and TFEB in cellular clearance, we propose that lysosomal TRPML1 may contribute a significant portion to the in vivo neuroprotective and anti-aging effects of Rap via an augmentation of autophagy and lysosomal biogenesis.
Extensive loss of cell-cycle and DNA repair genes in an ancient lineage of bipolar budding yeasts
Venue: PLoS biology

Cell-cycle checkpoints and DNA repair processes protect organisms from potentially lethal mutational damage. Compared to other budding yeasts in the subphylum Saccharomycotina, we noticed that a lineage in the genus Hanseniaspora exhibited very high evolutionary rates, low Guanine–Cytosine (GC) content, small genome sizes, and lower gene numbers. To better understand Hanseniaspora evolution, we analyzed 25 genomes, including 11 newly sequenced, representing 18/21 known species in the genus. Our phylogenomic analyses identify two Hanseniaspora lineages, a faster-evolving lineage (FEL), which began diversifying approximately 87 million years ago (mya), and a slower-evolving lineage (SEL), which began diversifying approximately 54 mya. Remarkably, both lineages lost genes associated with the cell cycle and genome integrity, but these losses were greater in the FEL. E.g., all species lost the cell-cycle regulator WHIskey 5 (WHI5), and the FEL lost components of the spindle checkpoint pathway (e.g., Mitotic Arrest-Deficient 1 [MAD1], Mitotic Arrest-Deficient 2 [MAD2]) and DNA-damage–checkpoint pathway (e.g., Mitosis Entry Checkpoint 3 [MEC3], RADiation sensitive 9 . Similarly, both lineages lost genes involved in DNA repair pathways, including the DNA glycosylase gene 3-MethylAdenine DNA Glycosylase 1 (MAG1), which is part of the base-excision repair pathway, and the DNA photolyase gene PHotoreactivation Repair deficient 1 (PHR1), which is involved in pyrimidine dimer repair. Strikingly, the FEL lost 33 additional genes, including polymerases (i.e., POLymerase 4 [POL4] and POL32) and telomere-associated genes (e.g., Repressor/activator site binding protein-Interacting Factor 1 [RIF1], Replication Factor A 3 [RFA3], Cell Division Cycle 13 [CDC13], Pbp1p Binding Protein [PBP2]). Echoing these losses, molecular evolutionary analyses reveal that, compared to the SEL, the FEL stem lineage underwent a burst of accelerated evolution, which resulted in greater mutational loads, homopolymer instabilities, and higher fractions of mutations associated with the common endogenously damaged base, 8-oxoguanine. We conclude that Hanseniaspora is an ancient lineage that has diversified and thrived, despite lacking many otherwise highly conserved cell-cycle and genome integrity genes and pathways, and may represent a novel, to our knowledge, system for studying cellular life without them.