nils-herrmann/clean_scirepeval huggingface dataset:
Additional support for RCR: A validated article-level measure of scientific influence
Venue: PLoS biology

In their comment, Janssens et al.  offer a critique of the Relative Citation Ratio (RCR), objecting to the construction of both the numerator and denominator of the metric. While we strongly agree that any measure used to assess the productivity of research programs should be thoughtfully designed and carefully validated, we believe that the specific concerns outlined in their correspondence are unfounded. Our original article acknowledged that RCR or, for that matter, any bibliometric measure has limited power to quantify the influence of any very recently published paper, because citation rates are inherently noisy when the absolute number of citations is small [2]. For this reason, in our iCite tool, we have not reported RCRs for papers published in the calendar year previous to the current year . However, while agreeing with our initial assertion that RCR cannot be used to conclusively evaluate recent papers, Janssens et al. also suggest that the failure to report RCRs for new publications might unfairly penalize some researchers. While it is widely understood that it takes time to accurately assess the influence that new papers have on their field, we have attempted to accommodate this concern by updating iCite so that RCRs are now reported for all papers in the database that have at least 5 citations and by adding a visual indicator to flag values for papers published in the last 18 months, which should be considered provisional . This modified practice will be maintained going forward. Regarding article citation rates of older articles, we have added data on the stability of RCR values to the “Statistics” page of the iCite website [4, 5]. We believe that these new data, which demonstrate that the vast majority of influential papers retain their influence over the period of an investigator’s career, should reassure users that RCR does not unfairly disadvantage older papers. Our analysis of the year-by-year changes in RCR values of National Institutes of Health (NIH)-funded articles published in 1991 reinforces this point . From 1992–2014, both on the individual level and in aggregate, RCR values are remarkably stable. For cases in which RCRs change significantly, the values typically increase. That said, we strongly believe that the potential for RCR to decrease over time is necessary and important; as knowledge advances and old models are replaced, publications rooted in those outdated models naturally become less influential. The RCR denominator (the expected citation rate [ECR]) is calculated by aggregating the article citation rates of peer papers that have the same field citation rate (FCR) and are published in the same year as the article in the numerator. FCR, as noted by Janssens et al., is defined as the collective 2-year journal citation rate for all papers in the co-citation network of the article being evaluated. This calculation is conceptually distinct from that used in determining journal impact factors; rather than relying on journal of publication to define an
Transcriptome analysis of hypoxic cancer cells uncovers intron retention in EIF2B5 as a mechanism to inhibit translation
Venue: PLoS biology

Cells adjust to hypoxic stress within the tumor microenvironment by downregulating energy-consuming processes including translation. To delineate mechanisms of cellular adaptation to hypoxia, we performed RNA-Seq of normoxic and hypoxic head and neck cancer cells. These data revealed a significant down regulation of genes known to regulate RNA processing and splicing. Exon-level analyses classified > 1,000 mRNAs as alternatively spliced under hypoxia and uncovered a unique retained intron (RI) in the master regulator of translation initiation, EIF2B5. Notably, this intron was expressed in solid tumors in a stage-dependent manner. We investigated the biological consequence of this RI and demonstrate that its inclusion creates a premature termination codon (PTC), that leads to a 65kDa truncated protein isoform that opposes full-length eIF2Bε to inhibit global translation. Furthermore, expression of 65kDa eIF2Bε led to increased survival of head and neck cancer cells under hypoxia, providing evidence that this isoform enables cells to adapt to conditions of low oxygen. Additional work to uncover -cis and -trans regulators of EIF2B5 splicing identified several factors that influence intron retention in EIF2B5: a weak splicing potential at the RI, hypoxia-induced expression and binding of the splicing factor SRSF3, and increased binding of total and phospho-Ser2 RNA polymerase II specifically at the intron retained under hypoxia. Altogether, these data reveal differential splicing as a previously uncharacterized mode of translational control under hypoxia and are supported by a model in which hypoxia-induced changes to cotranscriptional processing lead to selective retention of a PTC-containing intron in EIF2B5.
The Experimental Design Assistant
Venue: PLoS biology

Addressing the common problems that researchers encounter when designing and analysing animal experiments will improve the reliability of in vivo research. In this article, the Experimental Design Assistant (EDA) is introduced. The EDA is a web-based tool that guides the in vivo researcher through the experimental design and analysis process, providing automated feedback on the proposed design and generating a graphical summary that aids communication with colleagues, funders, regulatory authorities, and the wider scientific community. It will have an important role in addressing causes of irreproducibility.
Dynamic patterning by the Drosophila pair-rule network reconciles long-germ and short-germ segmentation
Venue: PLoS biology

Drosophila segmentation is a well-established paradigm for developmental pattern formation. However, the later stages of segment patterning, regulated by the “pair-rule” genes, are still not well understood at the system level. Building on established genetic interactions, I construct a logical model of the Drosophila pair-rule system that takes into account the demonstrated stage-specific architecture of the pair-rule gene network. Simulation of this model can accurately recapitulate the observed spatiotemporal expression of the pair-rule genes, but only when the system is provided with dynamic “gap” inputs. This result suggests that dynamic shifts of pair-rule stripes are essential for segment patterning in the trunk and provides a functional role for observed posterior-to-anterior gap domain shifts that occur during cellularisation. The model also suggests revised patterning mechanisms for the parasegment boundaries and explains the aetiology of the even-skipped null mutant phenotype. Strikingly, a slightly modified version of the model is able to pattern segments in either simultaneous or sequential modes, depending only on initial conditions. This suggests that fundamentally similar mechanisms may underlie segmentation in short-germ and long-germ arthropods.
Genome-wide identification of bacterial plant colonization genes
Venue: PLoS biology

Diverse soil-resident bacteria can contribute to plant growth and health, but the molecular mechanisms enabling them to effectively colonize their plant hosts remain poorly understood. We used randomly barcoded transposon mutagenesis sequencing (RB-TnSeq) in Pseudomonas simiae, a model root-colonizing bacterium, to establish a genome-wide map of bacterial genes required for colonization of the Arabidopsis thaliana root system. We identified 115 genes (2% of all P. simiae genes) with functions that are required for maximal competitive colonization of the root system. Among the genes we identified were some with obvious colonization-related roles in motility and carbon metabolism, as well as 44 other genes that had no or vague functional predictions. Independent validation assays of individual genes confirmed colonization functions for 20 of 22 (91%) cases tested. To further characterize genes identified by our screen, we compared the functional contributions of P. simiae genes to growth in 90 distinct in vitro conditions by RB-TnSeq, highlighting specific metabolic functions associated with root colonization genes. Our analysis of bacterial genes by sequence-driven saturation mutagenesis revealed a genome-wide map of the genetic determinants of plant root colonization and offers a starting point for targeted improvement of the colonization capabilities of plant-beneficial microbes.
A new discrete dynamic model of ABA-induced stomatal closure predicts key feedback loops
Venue: PLoS biology

Stomata, microscopic pores in leaf surfaces through which water loss and carbon dioxide uptake occur, are closed in response to drought by the phytohormone abscisic acid (ABA). This process is vital for drought tolerance and has been the topic of extensive experimental investigation in the last decades. Although a core signaling chain has been elucidated consisting of ABA binding to receptors, which alleviates negative regulation by protein phosphatases 2C (PP2Cs) of the protein kinase OPEN STOMATA 1 (OST1) and ultimately results in activation of anion channels, osmotic water loss, and stomatal closure, over 70 additional components have been identified, yet their relationships with each other and the core components are poorly elucidated. We integrated and processed hundreds of disparate observations regarding ABA signal transduction responses underlying stomatal closure into a network of 84 nodes and 156 edges and, as a result, established those relationships, including identification of a 36-node, strongly connected (feedback-rich) component as well as its in- and out-components. The network’s domination by a feedback-rich component may reflect a general feature of rapid signaling events. We developed a discrete dynamic model of this network and elucidated the effects of ABA plus knockout or constitutive activity of 79 nodes on both the outcome of the system (closure) and the status of all internal nodes. The model, with more than 1024 system states, is far from fully determined by the available data, yet model results agree with existing experiments in 82 cases and disagree in only 17 cases, a validation rate of 75%. Our results reveal nodes that could be engineered to impact stomatal closure in a controlled fashion and also provide over 140 novel predictions for which experimental data are currently lacking. Noting the paucity of wet-bench data regarding combinatorial effects of ABA and internal node activation, we experimentally confirmed several predictions of the model with regard to reactive oxygen species, cytosolic Ca2+ (Ca2+c), and heterotrimeric G-protein signaling. We analyzed dynamics-determining positive and negative feedback loops, thereby elucidating the attractor (dynamic behavior) repertoire of the system and the groups of nodes that determine each attractor. Based on this analysis, we predict the likely presence of a previously unrecognized feedback mechanism dependent on Ca2+c. This mechanism would provide model agreement with 10 additional experimental observations, for a validation rate of 85%. Our research underscores the importance of feedback regulation in generating robust and adaptable biological responses. The high validation rate of our model illustrates the advantages of discrete dynamic modeling for complex, nonlinear systems common in biology.
Development of rat female genital cortex and control of female puberty by sexual touch
Venue: PLoS biology

Rat somatosensory cortex contains a large sexually monomorphic genital representation. Genital cortex undergoes an unusual 2-fold expansion during puberty. Here, we investigate genital cortex development and female rat sexual maturation. Ovariectomies and estradiol injections suggested sex hormones cause the pubertal genital cortex expansion but not its maintenance at adult size. Genital cortex expanded by thalamic afferents invading surrounding dysgranular cortex. Genital touch was a dominant factor driving female sexual maturation. Raising female rats in contact with adult males promoted genital cortex expansion, whereas contact to adult females or nontactile (audio-visual-olfactory) male cues did not. Genital touch imposed by human experimenters powerfully advanced female genital cortex development and sexual maturation. Long-term blocking of genital cortex by tetrodotoxin in pubescent females housed with males prevented genital cortex expansion and decelerated vaginal opening. Sex hormones, sexual experience, and neural activity shape genital cortex, which contributes to the puberty promoting effects of sexual touch.
What do we talk about when we talk about rhythm?
Venue: PLoS biology

1 Department of Psychology, University of Lübeck, Lübeck, Germany, 2 Brain and Mind Institute, Department of Psychology, The University of Western Ontario London, Ontario, Canada, 3 Cognitive Neuroscience and Schizophrenia Program, Nathan Kline Institute, Orangeburg, New York, United States of America, 4 Department of Psychiatry, New York University School of Medicine, New York, New York, United States of America
Dance to the rhythm, cautiously: Isolating unique indicators of oscillatory entrainment
Venue: PLoS biology

The idea of entrainment of neural oscillations to temporal structure has become a central theory for attentional selection in time [1,2]. In our study , we separated unique electroencephalogram (EEG) signatures of oscillatory entrainment to rhythmic streams from those (specifically, inter-trial phase coherence [ITPC]) that overlap with other mechanisms of prediction. Obleser, Henry, and Lakatos’s (OHL’s) comment [4] highlights important issues regarding the study of entrainment mechanisms. We share OHL’s main message: rhythms may be complex and not necessarily isochronous. In fact, finding a stream devoid of any regularity is challenging. This is probably why entrainment mechanisms are functionally important! Yet we should not see entrainment mechanisms as omnipresent, nor should we render them irrefutable. Below, we reflect on some of OHL’s concerns regarding our study. Oscillatory entrainment predicts increased ITPC for rhythms [2,5], as both our and OHL’s models show. However, taking ITPC as evidence for entrainment, without ruling out other explanations, would be making the logical fallacy of "affirming the consequence" (a!b does not imply that b!a). Our study  thus asked which electrophysiological phenomena are uniquely associated with entrainment to rhythms instead of with general temporal prediction mechanisms that also operate in rhythmic contexts [6]. We conjectured that if ITPC reflects entrainment it should be sensitive to the level of regularity. However, we found that reducing the level of temporal regularity of streams did not reduce ITPC when predictability was preserved but only did so if predictability was also reduced. OHL’s argument that this is explained by predictions-related climbing neuronal activity (CNA; e.g., the contingent negative variation) only recapitulates one of our main arguments . Given this fact, can a repeated-CNA explanation be ruled out from previous ITPC findings, especially in designs with no warning signal? Using near-threshold stimuli [7] reduces onset-responses–driven ITPC but not anticipatory activity. OHL point out (like we did ) that our repeated-interval condition (RIC) was not arrhythmic, explaining observed ITPC levels. Critically though, the RIC was not designed to be arrhythmic but to be less periodic than the isochronous condition (IsoC), which should diminish entrainment signatures. For perceptual judgments evidence (cf. OHL’s demo) that this was achieved,  Preferably, the degree to which a sequence is conducive to entrainment of a given oscillation, well defined by frequency and phase, could be objectively quantified. In fact, OHL’s model, like ours, predicts a difference in phase (their figure 1b) and a lower ITPC (their figure 1c showing the effect of stimulus onset asynchrony
Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies
Venue: PLoS biology

Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the “insulin paradox”). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders.
Place field assembly distribution encodes preferred locations
Venue: PLoS biology

The hippocampus is the main locus of episodic memory formation and the neurons there encode the spatial map of the environment. Hippocampal place cells represent location, but their role in the learning of preferential location remains unclear. The hippocampus may encode locations independently from the stimuli and events that are associated with these locations. We have discovered a unique population code for the experience-dependent value of the context. The degree of reward-driven navigation preference highly correlates with the spatial distribution of the place fields recorded in the CA1 region of the hippocampus. We show place field clustering towards rewarded locations. Optogenetic manipulation of the ventral tegmental area demonstrates that the experience-dependent place field assembly distribution is directed by tegmental dopaminergic activity. The ability of the place cells to remap parallels the acquisition of reward context. Our findings present key evidence that the hippocampal neurons are not merely mapping the static environment but also store the concurrent context reward value, enabling episodic memory for past experience to support future adaptive behavior.
Extreme genome diversity in the hyper-prevalent parasitic eukaryote Blastocystis
Venue: PLoS biology

Blastocystis is the most prevalent eukaryotic microbe colonizing the human gut, infecting approximately 1 billion individuals worldwide. Although Blastocystis has been linked to intestinal disorders, its pathogenicity remains controversial because most carriers are asymptomatic. Here, the genome sequence of Blastocystis subtype (ST) 1 is presented and compared to previously published sequences for ST4 and ST7. Despite a conserved core of genes, there is unexpected diversity between these STs in terms of their genome sizes, guanine-cytosine (GC) content, intron numbers, and gene content. ST1 has 6,544 protein-coding genes, which is several hundred more than reported for ST4 and ST7. The percentage of proteins unique to each ST ranges from 6.2% to 20.5%, greatly exceeding the differences observed within parasite genera. Orthologous proteins also display extreme divergence in amino acid sequence identity between STs (i.e., 59%–61% median identity), on par with observations of the most distantly related species pairs of parasite genera. The STs also display substantial variation in gene family distributions and sizes, especially for protein kinase and protease gene families, which could reflect differences in virulence. It remains to be seen to what extent these inter-ST differences persist at the intra-ST level. A full 26% of genes in ST1 have stop codons that are created on the mRNA level by a novel polyadenylation mechanism found only in Blastocystis. Reconstructions of pathways and organellar systems revealed that ST1 has a relatively complete membrane-trafficking system and a near-complete meiotic toolkit, possibly indicating a sexual cycle. Unlike some intestinal protistan parasites, Blastocystis ST1 has near-complete de novo pyrimidine, purine, and thiamine biosynthesis pathways and is unique amongst studied stramenopiles in being able to metabolize α-glucans rather than β-glucans. It lacks all genes encoding heme-containing cytochrome P450 proteins. Predictions of the mitochondrion-related organelle (MRO) proteome reveal an expanded repertoire of functions, including lipid, cofactor, and vitamin biosynthesis, as well as proteins that may be involved in regulating mitochondrial morphology and MRO/endoplasmic reticulum (ER) interactions. In sharp contrast, genes for peroxisome-associated functions are absent, suggesting Blastocystis STs lack this organelle. Overall, this study provides an important window into the biology of Blastocystis, showcasing significant differences between STs that can guide future experimental investigations into differences in their virulence and clarifying the roles of these organisms in gut health and disease.
A map of protein dynamics during cell-cycle progression and cell-cycle exit
Venue: PLoS biology

The cell-cycle field has identified the core regulators that drive the cell cycle, but we do not have a clear map of the dynamics of these regulators during cell-cycle progression versus cell-cycle exit. Here we use single-cell time-lapse microscopy of Cyclin-Dependent Kinase 2 (CDK2) activity followed by endpoint immunofluorescence and computational cell synchronization to determine the temporal dynamics of key cell-cycle proteins in asynchronously cycling human cells. We identify several unexpected patterns for core cell-cycle proteins in actively proliferating (CDK2-increasing) versus spontaneously quiescent (CDK2-low) cells, including Cyclin D1, the levels of which we find to be higher in spontaneously quiescent versus proliferating cells. We also identify proteins with concentrations that steadily increase or decrease the longer cells are in quiescence, suggesting the existence of a continuum of quiescence depths. Our single-cell measurements thus provide a rich resource for the field by characterizing protein dynamics during proliferation versus quiescence.