nils-herrmann/clean_scirepeval huggingface dataset:
Brain Connectivity Predicts Placebo Response across Chronic Pain Clinical Trials
Venue: PLoS biology

Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo’s effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active treatment in some patients diminishes modeled placebo-related analgesia.
Visual BOLD Response in Late Blind Subjects with Argus II Retinal Prosthesis
Venue: PLoS biology

Retinal prosthesis technologies require that the visual system downstream of the retinal circuitry be capable of transmitting and elaborating visual signals. We studied the capability of plastic remodeling in late blind subjects implanted with the Argus II Retinal Prosthesis with psychophysics and functional MRI (fMRI). After surgery, six out of seven retinitis pigmentosa (RP) blind subjects were able to detect high-contrast stimuli using the prosthetic implant. However, direction discrimination to contrast modulated stimuli remained at chance level in all of them. No subject showed any improvement of contrast sensitivity in either eye when not using the Argus II. Before the implant, the Blood Oxygenation Level Dependent (BOLD) activity in V1 and the lateral geniculate nucleus (LGN) was very weak or absent. Surprisingly, after prolonged use of Argus II, BOLD responses to visual input were enhanced. This is, to our knowledge, the first study tracking the neural changes of visual areas in patients after retinal implant, revealing a capacity to respond to restored visual input even after years of deprivation.
STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways
Venue: PLoS biology

STAT2 is the quintessential transcription factor for type 1 interferons (IFNs), where it functions as a heterodimer with STAT1. However, the human and murine STAT2-deficient phenotypes suggest important additional and currently unidentified type 1 IFN-independent activities. Here, we show that STAT2 constitutively bound to STAT1, but not STAT3, via a conserved interface. While this interaction was irrelevant for type 1 interferon signaling and STAT1 activation, it precluded the nuclear translocation specifically of STAT1 in response to IFN-γ, interleukin-6 (IL-6), and IL-27. This is explained by the dimerization between activated STAT1 and unphosphorylated STAT2, whereby the semiphosphorylated dimers adopted a conformation incapable of importin-α binding. This, in turn, substantially attenuated cardinal IFN-γ responses, including MHC expression, senescence, and antiparasitic immunity, and shifted the transcriptional output of IL-27 from STAT1 to STAT3. Our results uncover STAT2 as a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways and provide an understanding of the type 1 interferon-independent activities of this protein.
snRNA 3′ End Processing by a CPSF73-Containing Complex Essential for Development in Arabidopsis
Venue: PLoS biology

Uridine-rich small nuclear RNAs (snRNAs) are the basal components of the spliceosome and play essential roles in splicing. The biogenesis of the majority of snRNAs involves 3′ end endonucleolytic cleavage of the nascent transcript from the elongating DNA-dependent RNA ploymerase II. However, the protein factors responsible for this process remain elusive in plants. Here, we show that DEFECTIVE in snRNA PROCESSING 1 (DSP1) is an essential protein for snRNA 3′ end maturation in Arabidopsis. A hypomorphic dsp1-1 mutation causes pleiotropic developmental defects, impairs the 3′ end processing of snRNAs, increases the levels of snRNA primary transcripts (pre-snRNAs), and alters the occupancy of Pol II at snRNA loci. In addition, DSP1 binds snRNA loci and interacts with Pol-II in a DNA/RNA-dependent manner. We further show that DSP1 forms a conserved complex, which contains at least four additional proteins, to catalyze snRNA 3′ end maturation in Arabidopsis. The catalytic component of this complex is likely the cleavage and polyadenylation specificity factor 73 kDa-I (CSPF73-I), which is the nuclease cleaving the pre-mRNA 3′ end. However, the DSP1 complex does not affect pre-mRNA 3′ end cleavage, suggesting that plants may use different CPSF73-I-containing complexes to process snRNAs and pre-mRNAs. This study identifies a complex responsible for the snRNA 3′ end maturation in plants and uncovers a previously unknown function of CPSF73 in snRNA maturation.
Relative Contributions of Specific Activity Histories and Spontaneous Processes to Size Remodeling of Glutamatergic Synapses
Venue: PLoS biology

The idea that synaptic properties are defined by specific pre- and postsynaptic activity histories is one of the oldest and most influential tenets of contemporary neuroscience. Recent studies also indicate, however, that synaptic properties often change spontaneously, even in the absence of specific activity patterns or any activity whatsoever. What, then, are the relative contributions of activity history-dependent and activity history-independent processes to changes synapses undergo? To compare the relative contributions of these processes, we imaged, in spontaneously active networks of cortical neurons, glutamatergic synapses formed between the same axons and neurons or dendrites under the assumption that their similar activity histories should result in similar size changes over timescales of days. The size covariance of such commonly innervated (CI) synapses was then compared to that of synapses formed by different axons (non-CI synapses) that differed in their activity histories. We found that the size covariance of CI synapses was greater than that of non-CI synapses; yet overall size covariance of CI synapses was rather modest. Moreover, momentary and time-averaged sizes of CI synapses correlated rather poorly, in perfect agreement with published electron microscopy-based measurements of mouse cortex synapses. A conservative estimate suggested that ~40% of the observed size remodeling was attributable to specific activity histories, whereas ~10% and ~50% were attributable to cell-wide and spontaneous, synapse-autonomous processes, respectively. These findings demonstrate that histories of naturally occurring activity patterns can direct glutamatergic synapse remodeling but also suggest that the contributions of spontaneous, possibly stochastic, processes are at least as great.
Selection Transforms the Landscape of Genetic Variation Interacting with Hsp90
Venue: PLoS biology

The protein-folding chaperone Hsp90 has been proposed to buffer the phenotypic effects of mutations. The potential for Hsp90 and other putative buffers to increase robustness to mutation has had major impact on disease models, quantitative genetics, and evolutionary theory. But Hsp90 sometimes contradicts expectations for a buffer by potentiating rapid phenotypic changes that would otherwise not occur. Here, we quantify Hsp90’s ability to buffer or potentiate (i.e., diminish or enhance) the effects of genetic variation on single-cell morphological features in budding yeast. We corroborate reports that Hsp90 tends to buffer the effects of standing genetic variation in natural populations. However, we demonstrate that Hsp90 tends to have the opposite effect on genetic variation that has experienced reduced selection pressure. Specifically, Hsp90 tends to enhance, rather than diminish, the effects of spontaneous mutations and recombinations. This result implies that Hsp90 does not make phenotypes more robust to the effects of genetic perturbation. Instead, natural selection preferentially allows buffered alleles to persist and thereby creates the false impression that Hsp90 confers greater robustness.
Enrichment of Phosphatidylethanolamine in Viral Replication Compartments via Co-opting the Endosomal Rab5 Small GTPase by a Positive-Strand RNA Virus
Venue: PLoS biology

Positive-strand RNA viruses build extensive membranous replication compartments to support replication and protect the virus from antiviral responses by the host. These viruses require host factors and various lipids to form viral replication complexes (VRCs). The VRCs built by Tomato bushy stunt virus (TBSV) are enriched with phosphatidylethanolamine (PE) through a previously unknown pathway. To unravel the mechanism of PE enrichment within the TBSV replication compartment, in this paper, the authors demonstrate that TBSV co-opts the guanosine triphosphate (GTP)-bound active form of the endosomal Rab5 small GTPase via direct interaction with the viral replication protein. Deletion of Rab5 orthologs in a yeast model host or expression of dominant negative mutants of plant Rab5 greatly decreases TBSV replication and prevents the redistribution of PE to the sites of viral replication. We also show that enrichment of PE in the viral replication compartment is assisted by actin filaments. Interestingly, the closely related Carnation Italian ringspot virus, which replicates on the boundary membrane of mitochondria, uses a similar strategy to the peroxisomal TBSV to hijack the Rab5-positive endosomes into the viral replication compartments. Altogether, usurping the GTP-Rab5–positive endosomes allows TBSV to build a PE-enriched viral replication compartment, which is needed to support peak-level replication. Thus, the Rab family of small GTPases includes critical host factors assisting VRC assembly and genesis of the viral replication compartment.
Human Germline Mutation and the Erratic Evolutionary Clock
Venue: PLoS biology

Our understanding of the chronology of human evolution relies on the “molecular clock” provided by the steady accumulation of substitutions on an evolutionary lineage. Recent analyses of human pedigrees have called this understanding into question by revealing unexpectedly low germline mutation rates, which imply that substitutions accrue more slowly than previously believed. Translating mutation rates estimated from pedigrees into substitution rates is not as straightforward as it may seem, however. We dissect the steps involved, emphasizing that dating evolutionary events requires not “a mutation rate” but a precise characterization of how mutations accumulate in development in males and females—knowledge that remains elusive.
Sex Chromosomes Do It Differently
Venue: PLoS biology

Organisms are finely tuned systems that are resilient to perturbations but that must maintain some constants. For example, within the genome, the ratio between different gene products must be tightly constrained to ensure stoichiometric assembly of protein complexes and the like. Evolution has honed expression levels so that as long as there is the same number of chromosomes per cell, the relative transcription levels of such genes can be kept constant .
Orienting the Interaction Compass: Resource Availability as a Major Driver of Context Dependence
Venue: PLoS biology

Life on earth is enormously diverse, in part because each individual engages in countless interactions with its biotic and abiotic environment during its lifetime. Not only are there many such interactions, but any given interaction of each individual with, say, its neighbor or a nutrient could lead to a different effect on its fitness and on the dynamics of the population of which it is a member. Predicting those effects is an enduring challenge to the field of ecology. Using a simple laboratory system, Hoek and colleagues present evidence that resource availability can be a primary driver of variation between interactions. Their results suggest that a complex continuum of interaction outcomes can result from the simple combined effects of nutrient availability and density-dependent population dynamics. The future is rich with potential to integrate tractable experimental systems like theirs with hypotheses derived from studies of interactions in natural communities.
The Reticular Cell Network: A Robust Backbone for Immune Responses
Venue: PLoS biology

Lymph nodes are meeting points for circulating immune cells. A network of reticular cells that ensheathe a mesh of collagen fibers crisscrosses the tissue in each lymph node. This reticular cell network distributes key molecules and provides a structure for immune cells to move around on. During infections, the network can suffer damage. A new study has now investigated the network’s structure in detail, using methods from graph theory. The study showed that the network is remarkably robust to damage: it can still support immune responses even when half of the reticular cells are destroyed. This is a further important example of how network connectivity achieves tolerance to failure, a property shared with other important biological and nonbiological networks.
A Neural Code That Is Isometric to Vocal Output and Correlates with Its Sensory Consequences
Venue: PLoS biology

What cortical inputs are provided to motor control areas while they drive complex learned behaviors? We study this question in the nucleus interface of the nidopallium (NIf), which is required for normal birdsong production and provides the main source of auditory input to HVC, the driver of adult song. In juvenile and adult zebra finches, we find that spikes in NIf projection neurons precede vocalizations by several tens of milliseconds and are insensitive to distortions of auditory feedback. We identify a local isometry between NIf output and vocalizations: quasi-identical notes produced in different syllables are preceded by highly similar NIf spike patterns. NIf multiunit firing during song precedes responses in auditory cortical neurons by about 50 ms, revealing delayed congruence between NIf spiking and a neural representation of auditory feedback. Our findings suggest that NIf codes for imminent acoustic events within vocal performance.
Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics
Venue: PLoS biology

The viral population of HIV-1, like many pathogens that cause systemic infection, is structured and differentiated within the body. The dynamics of cellular immune trafficking through the blood and within compartments of the body has also received wide attention. Despite these advances, mathematical models, which are widely used to interpret and predict viral and immune dynamics in infection, typically treat the infected host as a well-mixed homogeneous environment. Here, we present mathematical, analytical, and computational results that demonstrate that consideration of the spatial structure of the viral population within the host radically alters predictions of previous models. We study the dynamics of virus replication and cytotoxic T lymphocytes (CTLs) within a metapopulation of spatially segregated patches, representing T cell areas connected by circulating blood and lymph. The dynamics of the system depend critically on the interaction between CTLs and infected cells at the within-patch level. We show that for a wide range of parameters, the system admits an unexpected outcome called the shifting-mosaic steady state. In this state, the whole body’s viral population is stable over time, but the equilibrium results from an underlying, highly dynamic process of local infection and clearance within T-cell centers. Notably, and in contrast to previous models, this new model can explain the large differences in set-point viral load (SPVL) observed between patients and their distribution, as well as the relatively low proportion of cells infected at any one time, and alters the predicted determinants of viral load variation.
Associative Mechanisms Allow for Social Learning and Cultural Transmission of String Pulling in an Insect
Venue: PLoS biology

Social insects make elaborate use of simple mechanisms to achieve seemingly complex behavior and may thus provide a unique resource to discover the basic cognitive elements required for culture, i.e., group-specific behaviors that spread from “innovators” to others in the group via social learning. We first explored whether bumblebees can learn a nonnatural object manipulation task by using string pulling to access a reward that was presented out of reach. Only a small minority “innovated” and solved the task spontaneously, but most bees were able to learn to pull a string when trained in a stepwise manner. In addition, naïve bees learnt the task by observing a trained demonstrator from a distance. Learning the behavior relied on a combination of simple associative mechanisms and trial-and-error learning and did not require “insight”: naïve bees failed a “coiled-string experiment,” in which they did not receive instant visual feedback of the target moving closer when tugging on the string. In cultural diffusion experiments, the skill spread rapidly from a single knowledgeable individual to the majority of a colony’s foragers. We observed that there were several sequential sets (“generations”) of learners, so that previously naïve observers could first acquire the technique by interacting with skilled individuals and, subsequently, themselves become demonstrators for the next “generation” of learners, so that the longevity of the skill in the population could outlast the lives of informed foragers. This suggests that, so long as animals have a basic toolkit of associative and motor learning processes, the key ingredients for the cultural spread of unusual skills are already in place and do not require sophisticated cognition.
Diversity Takes Shape: Understanding the Mechanistic and Adaptive Basis of Bacterial Morphology
Venue: PLoS biology

The modern age of metagenomics has delivered unprecedented volumes of data describing the genetic and metabolic diversity of bacterial communities, but it has failed to provide information about coincident cellular morphologies. Much like metabolic and biosynthetic capabilities, morphology comprises a critical component of bacterial fitness, molded by natural selection into the many elaborate shapes observed across the bacterial domain. In this essay, we discuss the diversity of bacterial morphology and its implications for understanding both the mechanistic and the adaptive basis of morphogenesis. We consider how best to leverage genomic data and recent experimental developments in order to advance our understanding of bacterial shape and its functional importance.
In Search of Autism’s Roots
Venue: PLoS biology

Until Dustin Hoffman’s uncanny performance as an autistic savant in Rain Man, few outside medical circles knew much about autism. Hoffman’s humane portrayal of a socially inept man prone to nervous tics and obsessive ruminations, punctuated by stunning feats of math and memory, challenged us to accommodate people with special needs and reconsider our notions of normalcy. (For the record, only about one in ten people with autism are savants.)
Disruption of an Evolutionarily Novel Synaptic Expression Pattern in Autism
Venue: PLoS biology

Cognitive defects in autism spectrum disorder (ASD) include socialization and communication: key behavioral capacities that separate humans from other species. Here, we analyze gene expression in the prefrontal cortex of 63 autism patients and control individuals, as well as 62 chimpanzees and macaques, from natal to adult age. We show that among all aberrant expression changes seen in ASD brains, a single aberrant expression pattern overrepresented in genes involved synaptic-related pathways is enriched in nucleotide variants linked to autism. Furthermore, only this pattern contains an excess of developmental expression features unique to humans, thus resulting in the disruption of human-specific developmental programs in autism. Several members of the early growth response (EGR) transcription factor family can be implicated in regulation of this aberrant developmental change. Our study draws a connection between the genetic risk architecture of autism and molecular features of cortical development unique to humans.
Breast Cancer Patients Have Greatly Benefited from the Progress in Molecular Oncology
Venue: PLoS biology

Cancer research has become a global enterprise, and the number of researchers, as well as the cost for their activities, has skyrocketed. The budget for the National Cancer Institute of the United States National Institutes of Health alone was US$5.2 billion in 2015. Since most of the research is funded by public money, it is perfectly legitimate to ask if these large expenses are worth it. In this brief commentary, we recapitulate some of the breakthroughs that mark the history of breast cancer research over the past decades and emphasize the resulting benefits for afflicted women. In 1971, only 40% of women diagnosed with breast cancer would live another 10 years. Today, nearly 80% of women reach that significant milestone in most developed countries. This dramatic change has afforded breast cancer patients many productive years and a better quality of life. Progress resulted largely from advances in the understanding of the molecular details of the disease and their translation into innovative, rationally designed therapies. These developments are founded on the revolution in molecular and cellular biology, an entirely new array of methods and technologies, the enthusiasm, optimism, and diligence of scientists and clinicians, and the considerable funding efforts from public and private sources. We were lucky to be able to spend our productive years in a period of scientific upheaval in which methods and concepts were revolutionized and that allowed us to contribute, within the global scientific community, to the progress in basic science and clinical practice.