nils-herrmann/clean_scirepeval huggingface dataset:
Sequential sampling of visual objects during sustained attention
Venue: PLoS biology

In a crowded visual scene, attention must be distributed efficiently and flexibly over time and space to accommodate different contexts. It is well established that selective attention enhances the corresponding neural responses, presumably implying that attention would persistently dwell on the task-relevant item. Meanwhile, recent studies, mostly in divided attentional contexts, suggest that attention does not remain stationary but samples objects alternately over time, suggesting a rhythmic view of attention. However, it remains unknown whether the dynamic mechanism essentially mediates attentional processes at a general level. Importantly, there is also a complete lack of direct neural evidence reflecting whether and how the brain rhythmically samples multiple visual objects during stimulus processing. To address these issues, in this study, we employed electroencephalography (EEG) and a temporal response function (TRF) approach, which can dissociate responses that exclusively represent a single object from the overall neuronal activity, to examine the spatiotemporal characteristics of attention in various attentional contexts. First, attention, which is characterized by inhibitory alpha-band (approximately 10 Hz) activity in TRFs, switches between attended and unattended objects every approximately 200 ms, suggesting a sequential sampling even when attention is required to mostly stay on the attended object. Second, the attentional spatiotemporal pattern is modulated by the task context, such that alpha-mediated switching becomes increasingly prominent as the task requires a more uniform distribution of attention. Finally, the switching pattern correlates with attentional behavioral performance. Our work provides direct neural evidence supporting a generally central role of temporal organization mechanism in attention, such that multiple objects are sequentially sorted according to their priority in attentional contexts. The results suggest that selective attention, in addition to the classically posited attentional “focus,” involves a dynamic mechanism for monitoring all objects outside of the focus. Our findings also suggest that attention implements a space (object)-to-time transformation by acting as a series of concatenating attentional chunks that operate on 1 object at a time.
Integration of individual and social information for decision-making in groups of different sizes
Venue: PLoS biology

When making judgments in a group, individuals often revise their initial beliefs about the best judgment to make given what others believe. Despite the ubiquity of this phenomenon, we know little about how the brain updates beliefs when integrating personal judgments (individual information) with those of others (social information). Here, we investigated the neurocomputational mechanisms of how we adapt our judgments to those made by groups of different sizes, in the context of jury decisions for a criminal. By testing different theoretical models, we showed that a social Bayesian inference model captured changes in judgments better than 2 other models. Our results showed that participants updated their beliefs by appropriately weighting individual and social sources of information according to their respective credibility. When investigating 2 fundamental computations of Bayesian inference, belief updates and credibility estimates of social information, we found that the dorsal anterior cingulate cortex (dACC) computed the level of belief updates, while the bilateral frontopolar cortex (FPC) was more engaged in individuals who assigned a greater credibility to the judgments of a larger group. Moreover, increased functional connectivity between these 2 brain regions reflected a greater influence of group size on the relative credibility of social information. These results provide a mechanistic understanding of the computational roles of the FPC-dACC network in steering judgment adaptation to a group’s opinion. Taken together, these findings provide a computational account of how the human brain integrates individual and social information for decision-making in groups.
Practices and promises of Facebook for science outreach: Becoming a “Nerd of Trust”
Venue: PLoS biology

Arguably, the dissemination of science communication has recently entered a new age in which science must compete for public attention with fake news, alternate facts, and pseudoscience. This clash is particularly evident on social media. Facebook has taken a prime role in disseminating fake news, alternate facts, and pseudoscience, but is often ignored in the context of science outreach, especially among individual scientists. Based on new survey data, scientists appear in large Facebook networks but seldom post information about general science, their own scientific research, or culturally controversial topics in science. The typical individual scientist’s audience is large and personally connected, potentially leading to both a broad and deep engagement in science. Moreover, this media values individual expertise, allowing scientists to serve as a “Nerd of Trust” for their online friend and family networks. Science outreach via social media demands a renewed interest, and Facebook may be an overlooked high-return, low-risk science outreach tool in which scientists can play a valuable role to combat disinformation.
Environmental change drives accelerated adaptation through stimulated copy number variation
Venue: PLoS biology

Copy number variation (CNV) is rife in eukaryotic genomes and has been implicated in many human disorders, particularly cancer, in which CNV promotes both tumorigenesis and chemotherapy resistance. CNVs are considered random mutations but often arise through replication defects; transcription can interfere with replication fork progression and stability, leading to increased mutation rates at highly transcribed loci. Here we investigate whether inducible promoters can stimulate CNV to yield reproducible, environment-specific genetic changes. We propose a general mechanism for environmentally-stimulated CNV and validate this mechanism for the emergence of copper resistance in budding yeast. By analysing a large cohort of individual cells, we directly demonstrate that CNV of the copper-resistance gene CUP1 is stimulated by environmental copper. CNV stimulation accelerates the formation of novel alleles conferring enhanced copper resistance, such that copper exposure actively drives adaptation to copper-rich environments. Furthermore, quantification of CNV in individual cells reveals remarkable allele selectivity in the rate at which specific environments stimulate CNV. We define the key mechanistic elements underlying this selectivity, demonstrating that CNV is regulated by both promoter activity and acetylation of histone H3 lysine 56 (H3K56ac) and that H3K56ac is required for CUP1 CNV and efficient copper adaptation. Stimulated CNV is not limited to high-copy CUP1 repeat arrays, as we find that H3K56ac also regulates CNV in 3 copy arrays of CUP1 or SFA1 genes. The impact of transcription on DNA damage is well understood, but our research reveals that this apparently problematic association forms a pathway by which mutations can be directed to particular loci in particular environments and furthermore that this mutagenic process can be regulated through histone acetylation. Stimulated CNV therefore represents an unanticipated and remarkably controllable pathway facilitating organismal adaptation to new environments.
Human cyclophilin 40 unravels neurotoxic amyloids
Venue: PLoS biology

The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer’s disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases). Here we show that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Additionally, CyP40 ameliorated silver-positive and oligomeric tau species in a mouse model of tau accumulation, preserving neuronal health and cognition. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, CyP40 lacking PPIase activity prevented its capacity for disaggregation in vitro. Finally, we describe a unique structural property of CyP40 that may permit disaggregation to occur in an energy-independent manner. This study identifies a novel human protein disaggregase and, for the first time, demonstrates its capacity to dissolve intracellular amyloids.
Two different mechanisms support selective attention at different phases of training
Venue: PLoS biology

Selective attention supports the prioritized processing of relevant sensory information to facilitate goal-directed behavior. Studies in human subjects demonstrate that attentional gain of cortical responses can sufficiently account for attention-related improvements in behavior. On the other hand, studies using highly trained nonhuman primates suggest that reductions in neural noise can better explain attentional facilitation of behavior. Given the importance of selective information processing in nearly all domains of cognition, we sought to reconcile these competing accounts by testing the hypothesis that extensive behavioral training alters the neural mechanisms that support selective attention. We tested this hypothesis using electroencephalography (EEG) to measure stimulus-evoked visual responses from human subjects while they performed a selective spatial attention task over the course of ~1 month. Early in training, spatial attention led to an increase in the gain of stimulus-evoked visual responses. Gain was apparent within ~100 ms of stimulus onset, and a quantitative model based on signal detection theory (SDT) successfully linked the magnitude of this gain modulation to attention-related improvements in behavior. However, after extensive training, this early attentional gain was eliminated even though there were still substantial attention-related improvements in behavior. Accordingly, the SDT-based model required noise reduction to account for the link between the stimulus-evoked visual responses and attentional modulations of behavior. These findings suggest that training can lead to fundamental changes in the way attention alters the early cortical responses that support selective information processing. Moreover, these data facilitate the translation of results across different species and across experimental procedures that employ different behavioral training regimes.
Phosphatidylserine externalization, “necroptotic bodies” release, and phagocytosis during necroptosis
Venue: PLoS biology

Necroptosis is a regulated, nonapoptotic form of cell death initiated by receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins. It is considered to be a form of regulated necrosis, and, by lacking the “find me” and “eat me” signals that are a feature of apoptosis, necroptosis is considered to be inflammatory. One such “eat me” signal observed during apoptosis is the exposure of phosphatidylserine (PS) on the outer plasma membrane. Here, we demonstrate that necroptotic cells also expose PS after phosphorylated mixed lineage kinase-like (pMLKL) translocation to the membrane. Necroptotic cells that expose PS release extracellular vesicles containing proteins and pMLKL to their surroundings. Furthermore, inhibition of pMLKL after PS exposure can reverse the process of necroptosis and restore cell viability. Finally, externalization of PS by necroptotic cells drives recognition and phagocytosis, and this may limit the inflammatory response to this nonapoptotic form of cell death. The exposure of PS to the outer membrane and to extracellular vesicles is therefore a feature of necroptotic cell death and may serve to provide an immunologically-silent window by generating specific “find me” and “eat me” signals.
What drives cooperative breeding?
Venue: PLoS biology

Cooperative breeding, in which more than a pair of conspecifics cooperate to raise young at a single nest or brood, is widespread among vertebrates but highly variable in its geographic distribution. Particularly vexing has been identifying the ecological correlates of this phenomenon, which has been suggested to be favored in populations inhabiting both relatively stable, productive environments and in populations living under highly variable and unpredictable conditions. Griesser et al. provide a novel approach to this problem, performing a phylogenetic analysis indicating that family living is an intermediate step between nonsocial and cooperative breeding birds. They then examine the ecological and climatic conditions associated with these different social systems, concluding that cooperative breeding emerges when family living is favored in highly productive environments, followed secondarily by selection for cooperative breeding when environmental conditions deteriorate and within-year variability increases. Combined with recent work addressing the fitness consequences of cooperative breeding, Griesser et al.’s contribution stands to move the field forward by demonstrating that the evolution of complex adaptations such as cooperative breeding may only be understood when each of the steps leading to it are identified and carefully integrated.
Family living sets the stage for cooperative breeding and ecological resilience in birds
Venue: PLoS biology

Cooperative breeding is an extreme form of cooperation that evolved in a range of lineages, including arthropods, fish, birds, and mammals. Although cooperative breeding in birds is widespread and well-studied, the conditions that favored its evolution are still unclear. Based on phylogenetic comparative analyses on 3,005 bird species, we demonstrate here that family living acted as an essential stepping stone in the evolution of cooperative breeding in the vast majority of species. First, families formed by prolonging parent–offspring associations beyond nutritional independency, and second, retained offspring began helping at the nest. These findings suggest that assessment of the conditions that favor the evolution of cooperative breeding can be confounded if this process is not considered to include 2 steps. Specifically, phylogenetic linear mixed models show that the formation of families was associated with more productive and seasonal environments, where prolonged parent–offspring associations are likely to be less costly. However, our data show that the subsequent evolution of cooperative breeding was instead linked to environments with variable productivity, where helpers at the nest can buffer reproductive failure in harsh years. The proposed 2-step framework helps resolve current disagreements about the role of environmental forces in the evolution of cooperative breeding and better explains the geographic distribution of this trait. Many geographic hotspots of cooperative breeding have experienced a historical decline in productivity, suggesting that a higher proportion of family-living species could have been able to avoid extinction under harshening conditions through the evolution of cooperative breeding. These findings underscore the importance of considering the potentially different factors that drive different steps in the evolution of complex adaptations.
Laminin 211 inhibits protein kinase A in Schwann cells to modulate neuregulin 1 type III-driven myelination
Venue: PLoS biology

Myelin is required for proper nervous system function. Schwann cells in developing nerves depend on extrinsic signals from the axon and from the extracellular matrix to first sort and ensheathe a single axon and then myelinate it. Neuregulin 1 type III (Nrg1III) and laminin α2β1γ1 (Lm211) are the key axonal and matrix signals, respectively, but how their signaling is integrated and if each molecule controls both axonal sorting and myelination is unclear. Here, we use a series of epistasis experiments to show that Lm211 modulates neuregulin signaling to ensure the correct timing and amount of myelination. Lm211 can inhibit Nrg1III by limiting protein kinase A (PKA) activation, which is required to initiate myelination. We provide evidence that excessive PKA activation amplifies promyelinating signals downstream of neuregulin, including direct activation of the neuregulin receptor ErbB2 and its effector Grb2-Associated Binder-1 (Gab1), thereby elevating the expression of the key transcription factors Oct6 and early growth response protein 2 (Egr2). The inhibitory effect of Lm211 is seen only in fibers of small caliber. These data may explain why hereditary neuropathies associated with decreased laminin function are characterized by focally thick and redundant myelin.
High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance
Venue: PLoS biology

Antibiotic-resistant infections kill approximately 23,000 people and cost $20,000,000,000 each year in the United States alone despite the widespread use of small-molecule antimicrobial combination therapy. Antibiotic combinations typically have an additive effect: the efficacy of the combination matches the sum of the efficacies of each antibiotic when used alone. Small molecules can also act synergistically when the efficacy of the combination is greater than the additive efficacy. However, synergistic combinations are rare and have been historically difficult to identify. High-throughput identification of synergistic pairs is limited by the scale of potential combinations: a modest collection of 1,000 small molecules involves 1 million pairwise combinations. Here, we describe a high-throughput method for rapid identification of synergistic small-molecule pairs, the overlap2 method (O2M). O2M extracts patterns from chemical-genetic datasets, which are created when a collection of mutants is grown in the presence of hundreds of different small molecules, producing a precise set of phenotypes induced by each small molecule across the mutant set. The identification of mutants that show the same phenotype when treated with known synergistic molecules allows us to pinpoint additional molecule combinations that also act synergistically. As a proof of concept, we focus on combinations with the antibiotics trimethoprim and sulfamethizole, which had been standard treatment against urinary tract infections until widespread resistance decreased efficacy. Using O2M, we screened a library of 2,000 small molecules and identified several that synergize with the antibiotic trimethoprim and/or sulfamethizole. The most potent of these synergistic interactions is with the antiviral drug azidothymidine (AZT). We then demonstrate that understanding the molecular mechanism underlying small-molecule synergistic interactions allows the rational design of additional combinations that bypass drug resistance. Trimethoprim and sulfamethizole are both folate biosynthesis inhibitors. We find that this activity disrupts nucleotide homeostasis, which blocks DNA replication in the presence of AZT. Building on these data, we show that other small molecules that disrupt nucleotide homeostasis through other mechanisms (hydroxyurea and floxuridine) also act synergistically with AZT. These novel combinations inhibit the growth and virulence of trimethoprim-resistant clinical Escherichia coli and Klebsiella pneumoniae isolates, suggesting that they may be able to be rapidly advanced into clinical use. In sum, we present a generalizable method to screen for novel synergistic combinations, to identify particular mechanisms resulting in synergy, and to use the mechanistic knowledge to rationally design new combinations that bypass drug resistance.
MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression
Venue: PLoS biology

Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a “cytokine storm” with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm’s initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host’s ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa-associated invariant T (MAIT) cells, as the most powerful source of pro-inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA-DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD-scid IL-2Rγnull mice to demonstrate for the first time that: i) mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB); ii) the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT) or γδ T cells, and is characterized by production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-2, but not IL-17A; iii) high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1) participation, is required for MAIT cell activation; iv) MAIT cell responses to SEB can occur in a T cell receptor (TCR) Vβ–specific manner but are largely contributed by IL-12 and IL-18; v) as MAIT cells are primed by SAgs, they also begin to develop a molecular signature consistent with exhaustion and failure to participate in antimicrobial defense. Accordingly, they upregulate lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-3 (TIM-3), and/or programmed cell death-1 (PD-1), and acquire an anergic phenotype that interferes with their cognate function against Klebsiella pneumoniae and Escherichia coli; vi) MAIT cell hyperactivation and anergy co-utilize a signaling pathway that is governed by p38 and MEK1/2. Collectively, our findings demonstrate a pathogenic, rather than protective, role for MAIT cells during infection. Furthermore, we propose a novel mechanism of SAg-associated immunosuppression in humans. MAIT cells may therefore provide an attractive therapeutic target for the management of both early and late phases of severe SAg-mediated illnesses.