nils-herrmann/clean_scirepeval huggingface dataset:
Superspreading events in the transmission dynamics of SARS-CoV-2: Opportunities for interventions and control
Venue: PLoS biology

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 2019 (COVID-19) disease, has moved rapidly around the globe, infecting millions and killing hundreds of thousands. The basic reproduction number, which has been widely used—appropriately and less appropriately—to characterize the transmissibility of the virus, hides the fact that transmission is stochastic, often dominated by a small number of individuals, and heavily influenced by superspreading events (SSEs). The distinct transmission features of SARS-CoV-2, e.g., high stochasticity under low prevalence (as compared to other pathogens, such as influenza), and the central role played by SSEs on transmission dynamics cannot be overlooked. Many explosive SSEs have occurred in indoor settings, stoking the pandemic and shaping its spread, such as long-term care facilities, prisons, meat-packing plants, produce processing facilities, fish factories, cruise ships, family gatherings, parties, and nightclubs. These SSEs demonstrate the urgent need to understand routes of transmission, while posing an opportunity to effectively contain outbreaks with targeted interventions to eliminate SSEs. Here, we describe the different types of SSEs, how they influence transmission, empirical evidence for their role in the COVID-19 pandemic, and give recommendations for control of SARS-CoV-2.
Computational imaging during video game playing shows dynamic synchronization of cortical and subcortical networks of emotions
Venue: PLoS biology

Emotions are multifaceted phenomena affecting mind, body, and behavior. Previous studies sought to link particular emotion categories (e.g., fear) or dimensions (e.g., valence) to specific brain substrates but generally found distributed and overlapping activation patterns across various emotions. In contrast, distributed patterns accord with multi-componential theories whereby emotions emerge from appraisal processes triggered by current events, combined with motivational, expressive, and physiological mechanisms orchestrating behavioral responses. According to this framework, components are recruited in parallel and dynamically synchronized during emotion episodes. Here, we use functional MRI (fMRI) to investigate brain-wide systems engaged by theoretically defined components and measure their synchronization during an interactive emotion-eliciting video game. We show that each emotion component recruits large-scale cortico-subcortical networks, and that moments of dynamic synchronization between components selectively engage basal ganglia, sensory-motor structures, and midline brain areas. These neural results support theoretical accounts grounding emotions onto embodied and action-oriented functions triggered by synchronized component processes.
NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype
Venue: PLoS biology

Hypertension is the most important cause of death and disability in the elderly. In 9 out of 10 cases, the molecular cause, however, is unknown. One mechanistic hypothesis involves impaired endothelium-dependent vasodilation through reactive oxygen species (ROS) formation. Indeed, ROS forming NADPH oxidase (Nox) genes associate with hypertension, yet target validation has been negative. We re-investigate this association by molecular network analysis and identify NOX5, not present in rodents, as a sole neighbor to human vasodilatory endothelial nitric oxide (NO) signaling. In hypertensive patients, endothelial microparticles indeed contained higher levels of NOX5—but not NOX1, NOX2, or NOX4—with a bimodal distribution correlating with disease severity. Mechanistically, mice expressing human Nox5 in endothelial cells developed—upon aging—severe systolic hypertension and impaired endothelium-dependent vasodilation due to uncoupled NO synthase (NOS). We conclude that NOX5-induced uncoupling of endothelial NOS is a causal mechanism and theragnostic target of an age-related hypertension endotype. Nox5 knock-in (KI) mice represent the first mechanism-based animal model of hypertension.
Temporal coding of echo spectral shape in the bat auditory cortex
Venue: PLoS biology

Echolocating bats rely upon spectral interference patterns in echoes to reconstruct fine details of a reflecting object’s shape. However, the acoustic modulations required to do this are extremely brief, raising questions about how their auditory cortex encodes and processes such rapid and fine spectrotemporal details. Here, we tested the hypothesis that biosonar target shape representation in the primary auditory cortex (A1) is more reliably encoded by changes in spike timing (latency) than spike rates and that latency is sufficiently precise to support a synchronization-based ensemble representation of this critical auditory object feature space. To test this, we measured how the spatiotemporal activation patterns of A1 changed when naturalistic spectral notches were inserted into echo mimic stimuli. Neurons tuned to notch frequencies were predicted to exhibit longer latencies and lower mean firing rates due to lower signal amplitudes at their preferred frequencies, and both were found to occur. Comparative analyses confirmed that significantly more information was recoverable from changes in spike times relative to concurrent changes in spike rates. With this data, we reconstructed spatiotemporal activation maps of A1 and estimated the level of emerging neuronal spike synchrony between cortical neurons tuned to different frequencies. The results support existing computational models, indicating that spectral interference patterns may be efficiently encoded by a cascading tonotopic sequence of neural synchronization patterns within an ensemble of network activity that relates to the physical features of the reflecting object surface.
Monitor for COVID-19 vaccine resistance evolution during clinical trials
Venue: PLoS biology

Although less common than the evolution of antimicrobial drug resistance, vaccine resistance can and has evolved. How likely is it that COVID-19 vaccines currently in development will be undermined by viral evolution? We argue that this can be determined by repurposing samples that are already being collected as part of clinical trials. Such information would be useful for prioritizing investment among candidate vaccines and maximizing the potential long-term impact of COVID-19 vaccines.
Common ground: The foundation of interdisciplinary research on bat disease emergence
Venue: PLoS biology

Human perturbation of natural systems is accelerating the emergence of infectious diseases, mandating integration of disease and ecological research. Bats have been associated with recent zoonoses, but our bibliometric analysis of coauthor relationships identified a separation of bat ecologists and infectious disease researchers with few cross-disciplinary relationships. Of 5,645 papers, true interdisciplinary collaborations occurred primarily in research focused on White Nose Syndrome (WNS). This finding is important because it illustrates how research with outcomes favoring both bat conservation and disease mitigation promotes domain integration and network connectivity. We advocate for increased engagement between ecology and infectious researchers to address such common causes and suggest that efforts focus on leveraging existing activities, building interdisciplinary projects, and networking individuals and networks to integrate domains and coordinate resources. We provide specific opportunities for pursuing these strategies through the Bat One Health Research Network (BOHRN).
A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19
Venue: PLoS biology

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of coexisting medical conditions, while the underlying mechanisms remain unclear. Furthermore, there are no approved therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, disease manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus–host protein–protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measurement revealed underlying pathogenesis for broad COVID-19-associated disease manifestations. Analyses of single-cell RNA sequencing data show that co-expression of ACE2 and TMPRSS2 is elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn disease patients compared to uninflamed tissues, revealing shared pathobiology between COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicate that COVID-19 shares an intermediate inflammatory molecular profile with asthma (including IRAK3 and ADRB2). To prioritize potential treatments, we combined network-based prediction and a propensity score (PS) matching observational study of 26,779 individuals from a COVID-19 registry. We identified that melatonin usage (odds ratio [OR] = 0.72, 95% CI 0.56–0.91) is significantly associated with a 28% reduced likelihood of a positive laboratory test result for SARS-CoV-2 confirmed by reverse transcription–polymerase chain reaction assay. Using a PS matching user active comparator design, we determined that melatonin usage was associated with a reduced likelihood of SARS-CoV-2 positive test result compared to use of angiotensin II receptor blockers (OR = 0.70, 95% CI 0.54–0.92) or angiotensin-converting enzyme inhibitors (OR = 0.69, 95% CI 0.52–0.90). Importantly, melatonin usage (OR = 0.48, 95% CI 0.31–0.75) is associated with a 52% reduced likelihood of a positive laboratory test result for SARS-CoV-2 in African Americans after adjusting for age, sex, race, smoking history, and various disease comorbidities using PS matching. In summary, this study presents an integrative network medicine platform for predicting disease manifestations associated with COVID-19 and identifying melatonin for potential prevention and treatment of COVID-19.
TOP1α, UPF1, and TTG2 regulate seed size in a parental dosage–dependent manner
Venue: PLoS biology

Cues of maternal and paternal origins interact to control seed development, and the underlying molecular mechanisms are still far from clear. Here, we show that TOPOISOMERASE Iα (TOP1α), UP-FRAMESHIFT SUPPRESSOR 1 (UPF1), and TRANSPARENT TESTA GLABRA2 (TTG2) gametophytically, biparentally regulate seed size in Arabidopsis. TOP1α and UPF1 are mainly expressed in antipodal cells, and loss of their function leads to ectopic TTG2 expression in these female gametophytic cells. We further demonstrate that TOP1α and UPF1 directly repress TTG2 expression through affecting its chromatin status and determine its relative expression in antipodal cells versus sperm cells, which controls seed size in a dosage-dependent and parent-of-origin-dependent manner. The molecular interplay among these three genes explains their biparental gametophytic effect during diploidy and interploidy reciprocal crosses. Taken together, our findings reveal a molecular framework of parental interaction for seed size control.
SiCTeC: An inexpensive, easily assembled Peltier device for rapid temperature shifting during single-cell imaging
Venue: PLoS biology

Single-cell imaging, combined with recent advances in image analysis and microfluidic technologies, have enabled fundamental discoveries of cellular responses to chemical perturbations that are often obscured by traditional liquid-culture experiments. Temperature is an environmental variable well known to impact growth and to elicit specific stress responses at extreme values; it is often used as a genetic tool to interrogate essential genes. However, the dynamic effects of temperature shifts have remained mostly unstudied at the single-cell level, due largely to engineering challenges related to sample stability, heatsink considerations, and temperature measurement and feedback. Additionally, the few commercially available temperature-control platforms are costly. Here, we report an inexpensive (<$110) and modular Single-Cell Temperature Controller (SiCTeC) device for microbial imaging—based on straightforward modifications of the typical slide-sample-coverslip approach to microbial imaging—that controls temperature using a ring-shaped Peltier module and microcontroller feedback. Through stable and precise (±0.15°C) temperature control, SiCTeC achieves reproducible and fast (1–2 min) temperature transitions with programmable waveforms between room temperature and 45°C with an air objective. At the device’s maximum temperature of 89°C, SiCTeC revealed that Escherichia coli cells progressively shrink and lose cellular contents. During oscillations between 30°C and 37°C, cells rapidly adapted their response to temperature upshifts. Furthermore, SiCTeC enabled the discovery of rapid morphological changes and enhanced sensitivity to substrate stiffness during upshifts to nonpermissive temperatures in temperature-sensitive mutants of cell-wall synthesis enzymes. Overall, the simplicity and affordability of SiCTeC empowers future studies of the temperature dependence of single-cell physiology.
Task-related activity in human visual cortex
Venue: PLoS biology

The brain exhibits widespread endogenous responses in the absence of visual stimuli, even at the earliest stages of visual cortical processing. Such responses have been studied in monkeys using optical imaging with a limited field of view over visual cortex. Here, we used functional MRI (fMRI) in human participants to study the link between arousal and endogenous responses in visual cortex. The response that we observed was tightly entrained to task timing, was spatially extensive, and was independent of visual stimulation. We found that this response follows dynamics similar to that of pupil size and heart rate, suggesting that task-related activity is related to arousal. Finally, we found that higher reward increased response amplitude while decreasing its trial-to-trial variability (i.e., the noise). Computational simulations suggest that increased temporal precision underlies both of these observations. Our findings are consistent with optical imaging studies in monkeys and support the notion that arousal increases precision of neural activity.
Rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2C
Venue: PLoS biology

There is a great need for antiviral drugs to treat enterovirus (EV) and rhinovirus (RV) infections, which can be severe and occasionally life-threatening. The conserved nonstructural protein 2C, which is an AAA+ ATPase, is a promising target for drug development. Here, we present a structure-activity relationship study of a previously identified compound that targets the 2C protein of EV-A71 and several EV-B species members, but not poliovirus (PV) (EV-C species). This compound is structurally related to the Food and Drug Administration (FDA)-approved drug fluoxetine—which also targets 2C—but has favorable chemical properties. We identified several compounds with increased antiviral potency and broadened activity. Four compounds showed broad-spectrum EV and RV activity and inhibited contemporary strains of emerging EVs of public health concern, including EV-A71, coxsackievirus (CV)-A24v, and EV-D68. Importantly, unlike (S)-fluoxetine, these compounds are no longer neuroactive. By raising resistant EV-A71, CV-B3, and EV-D68 variants against one of these inhibitors, we identified novel 2C resistance mutations. Reverse engineering of these mutations revealed a conserved mechanism of resistance development. Resistant viruses first acquired a mutation in, or adjacent to, the α2 helix of 2C. This mutation disrupted compound binding and provided drug resistance, but this was at the cost of viral fitness. Additional mutations at distantly localized 2C residues were then acquired to increase resistance and/or to compensate for the loss of fitness. Using computational methods to identify solvent accessible tunnels near the α2 helix in the EV-A71 and PV 2C crystal structures, a conserved binding pocket of the inhibitors is proposed.
Hippocampal neurons with stable excitatory connectivity become part of neuronal representations
Venue: PLoS biology

Experiences are represented in the brain by patterns of neuronal activity. Ensembles of neurons representing experience undergo activity-dependent plasticity and are important for learning and recall. They are thus considered cellular engrams of memory. Yet, the cellular events that bias neurons to become part of a neuronal representation are largely unknown. In rodents, turnover of structural connectivity has been proposed to underlie the turnover of neuronal representations and also to be a cellular mechanism defining the time duration for which memories are stored in the hippocampus. If these hypotheses are true, structural dynamics of connectivity should be involved in the formation of neuronal representations and concurrently important for learning and recall. To tackle these questions, we used deep-brain 2-photon (2P) time-lapse imaging in transgenic mice in which neurons expressing the Immediate Early Gene (IEG) Arc (activity-regulated cytoskeleton-associated protein) could be permanently labeled during a specific time window. This enabled us to investigate the dynamics of excitatory synaptic connectivity—using dendritic spines as proxies—of hippocampal CA1 (cornu ammonis 1) pyramidal neurons (PNs) becoming part of neuronal representations exploiting Arc as an indicator of being part of neuronal representations. We discovered that neurons that will prospectively express Arc have slower turnover of synaptic connectivity, thus suggesting that synaptic stability prior to experience can bias neurons to become part of representations or possibly engrams. We also found a negative correlation between stability of structural synaptic connectivity and the ability to recall features of a hippocampal-dependent memory, which suggests that faster structural turnover in hippocampal CA1 might be functional for memory.
Independent representations of self-motion and object location in barrel cortex output
Venue: PLoS biology

During active tactile exploration, the dynamic patterns of touch are transduced to electrical signals and transformed by the brain into a mental representation of the object under investigation. This transformation from sensation to perception is thought to be a major function of the mammalian cortex. In primary somatosensory cortex (S1) of mice, layer 5 (L5) pyramidal neurons are major outputs to downstream areas that influence perception, decision-making, and motor control. We investigated self-motion and touch representations in L5 of S1 with juxtacellular loose-seal patch recordings of optogenetically identified excitatory neurons. We found that during rhythmic whisker movement, 54 of 115 active neurons (47%) represented self-motion. This population was significantly more modulated by whisker angle than by phase. Upon active touch, a distinct pattern of activity was evoked across L5, which represented the whisker angle at the time of touch. Object location was decodable with submillimeter precision from the touch-evoked spike counts of a randomly sampled handful of these neurons. These representations of whisker angle during self-motion and touch were independent, both in the selection of which neurons were active and in the angle-tuning preference of coactive neurons. Thus, the output of S1 transiently shifts from a representation of self-motion to an independent representation of explored object location during active touch.
The noncoding small RNA SsrA is released by Vibrio fischeri and modulates critical host responses
Venue: PLoS biology

The regulatory noncoding small RNAs (sRNAs) of bacteria are key elements influencing gene expression; however, there has been little evidence that beneficial bacteria use these molecules to communicate with their animal hosts. We report here that the bacterial sRNA SsrA plays an essential role in the light-organ symbiosis between Vibrio fischeri and the squid Euprymna scolopes. The symbionts load SsrA into outer membrane vesicles, which are transported specifically into the epithelial cells surrounding the symbiont population in the light organ. Although an SsrA-deletion mutant (ΔssrA) colonized the host to a normal level after 24 h, it produced only 2/10 the luminescence per bacterium, and its persistence began to decline by 48 h. The host’s response to colonization by the ΔssrA strain was also abnormal: the epithelial cells underwent premature swelling, and host robustness was reduced. Most notably, when colonized by the ΔssrA strain, the light organ differentially up-regulated 10 genes, including several encoding heightened immune-function or antimicrobial activities. This study reveals the potential for a bacterial symbiont’s sRNAs not only to control its own activities but also to trigger critical responses promoting homeostasis in its host. In the absence of this communication, there are dramatic fitness consequences for both partners.
Membrane progesterone receptor induces meiosis in Xenopus oocytes through endocytosis into signaling endosomes and interaction with APPL1 and Akt2
Venue: PLoS biology

The steroid hormone progesterone (P4) mediates many physiological processes through either nuclear receptors that modulate gene expression or membrane P4 receptors (mPRs) that mediate nongenomic signaling. mPR signaling remains poorly understood. Here we show that the topology of mPRβ is similar to adiponectin receptors and opposite to that of G-protein-coupled receptors (GPCRs). Using Xenopus oocyte meiosis as a well-established physiological readout of nongenomic P4 signaling, we demonstrate that mPRβ signaling requires the adaptor protein APPL1 and the kinase Akt2. We further show that P4 induces clathrin-dependent endocytosis of mPRβ into signaling endosome, where mPR interacts transiently with APPL1 and Akt2 to induce meiosis. Our findings outline the early steps involved in mPR signaling and expand the spectrum of mPR signaling through the multitude of pathways involving APPL1.
Aequorea’s secrets revealed: New fluorescent proteins with unique properties for bioimaging and biosensing
Venue: PLoS biology

Using mRNA sequencing and de novo transcriptome assembly, we identified, cloned, and characterized 9 previously undiscovered fluorescent protein (FP) homologs from Aequorea victoria and a related Aequorea species, with most sequences highly divergent from A. victoria green fluorescent protein (avGFP). Among these FPs are the brightest green fluorescent protein (GFP) homolog yet characterized and a reversibly photochromic FP that responds to UV and blue light. Beyond green emitters, Aequorea species express purple- and blue-pigmented chromoproteins (CPs) with absorbances ranging from green to far-red, including 2 that are photoconvertible. X-ray crystallography revealed that Aequorea CPs contain a chemically novel chromophore with an unexpected crosslink to the main polypeptide chain. Because of the unique attributes of several of these newly discovered FPs, we expect that Aequorea will, once again, give rise to an entirely new generation of useful probes for bioimaging and biosensing.