nils-herrmann/clean_scirepeval huggingface dataset:
The Venus flytrap trigger hair–specific potassium channel KDM1 can reestablish the K+ gradient required for hapto-electric signaling
Venue: PLoS biology

The carnivorous plant Dionaea muscipula harbors multicellular trigger hairs designed to sense mechanical stimuli upon contact with animal prey. At the base of the trigger hair, mechanosensation is transduced into an all-or-nothing action potential (AP) that spreads all over the trap, ultimately leading to trap closure and prey capture. To reveal the molecular basis for the unique functional repertoire of this mechanoresponsive plant structure, we determined the transcriptome of D. muscipula’s trigger hair. Among the genes that were found to be highly specific to the trigger hair, the Shaker-type channel KDM1 was electrophysiologically characterized as a hyperpolarization- and acid-activated K+-selective channel, thus allowing the reuptake of K+ ions into the trigger hair’s sensory cells during the hyperpolarization phase of the AP. During trap development, the increased electrical excitability of the trigger hair is associated with the transcriptional induction of KDM1. Conversely, when KDM1 is blocked by Cs+ in adult traps, the initiation of APs in response to trigger hair deflection is reduced, and trap closure is suppressed. KDM1 thus plays a dominant role in K+ homeostasis in the context of AP and turgor formation underlying the mechanosensation of trigger hair cells and thus D. muscipula’s hapto-electric signaling.
TNF-α signaling: TACE inhibition to put out the burning heart
Venue: PLoS biology

More than 20 years ago, Seta and colleagues hypothesized that cytokines, which are activated by myocardial injury, significantly drive heart failure progression and would therefore be effective targets to treat cardiac dysfunction. Unfortunately, several clinical trials inhibiting key cytokines like tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (Il-1β) turned out negative or even revealed adverse clinical effects. Providing a potential mechanistic explanation for the ineffectiveness of TNF-α blockade in heart failure, novel findings demonstrate that the membrane-bound precursor form of TNF-α, transmembrane TNF-α (tmTNF-α), mediates cardioprotective effects during pressure overload-induced cardiac remodeling. This study suggests that preventing tmTNF-α cleavage by targeting the TNF-α converting enzyme (TACE) rather than inhibiting TNF-α signaling altogether might be a valuable therapeutic approach.
Ensuring the quality and specificity of preregistrations
Venue: PLoS biology

Researchers face many, often seemingly arbitrary, choices in formulating hypotheses, designing protocols, collecting data, analyzing data, and reporting results. Opportunistic use of “researcher degrees of freedom” aimed at obtaining statistical significance increases the likelihood of obtaining and publishing false-positive results and overestimated effect sizes. Preregistration is a mechanism for reducing such degrees of freedom by specifying designs and analysis plans before observing the research outcomes. The effectiveness of preregistration may depend, in part, on whether the process facilitates sufficiently specific articulation of such plans. In this preregistered study, we compared 2 formats of preregistration available on the OSF: Standard Pre-Data Collection Registration and Prereg Challenge Registration (now called “OSF Preregistration,” http://osf.io/prereg/). The Prereg Challenge format was a “structured” workflow with detailed instructions and an independent review to confirm completeness; the “Standard” format was “unstructured” with minimal direct guidance to give researchers flexibility for what to prespecify. Results of comparing random samples of 53 preregistrations from each format indicate that the “structured” format restricted the opportunistic use of researcher degrees of freedom better (Cliff’s Delta = 0.49) than the “unstructured” format, but neither eliminated all researcher degrees of freedom. We also observed very low concordance among coders about the number of hypotheses (14%), indicating that they are often not clearly stated. We conclude that effective preregistration is challenging, and registration formats that provide effective guidance may improve the quality of research.
Reoccurring neural stem cell divisions in the adult zebrafish telencephalon are sufficient for the emergence of aggregated spatiotemporal patterns
Venue: PLoS biology

Regulation of quiescence and cell cycle entry is pivotal for the maintenance of stem cell populations. Regulatory mechanisms, however, are poorly understood. In particular, it is unclear how the activity of single stem cells is coordinated within the population or if cells divide in a purely random fashion. We addressed this issue by analyzing division events in an adult neural stem cell (NSC) population of the zebrafish telencephalon. Spatial statistics and mathematical modeling of over 80,000 NSCs in 36 brain hemispheres revealed weakly aggregated, nonrandom division patterns in space and time. Analyzing divisions at 2 time points allowed us to infer cell cycle and S-phase lengths computationally. Interestingly, we observed rapid cell cycle reentries in roughly 15% of newly born NSCs. In agent-based simulations of NSC populations, this redividing activity sufficed to induce aggregated spatiotemporal division patterns that matched the ones observed experimentally. In contrast, omitting redivisions leads to a random spatiotemporal distribution of dividing cells. Spatiotemporal aggregation of dividing stem cells can thus emerge solely from the cells’ history.
The Drosophila amyloid precursor protein homologue mediates neuronal survival and neuroglial interactions
Venue: PLoS biology

The amyloid precursor protein (APP) is a structurally and functionally conserved transmembrane protein whose physiological role in adult brain function and health is still unclear. Because mutations in APP cause familial Alzheimer’s disease (fAD), most research focuses on this aspect of APP biology. We investigated the physiological function of APP in the adult brain using the fruit fly Drosophila melanogaster, which harbors a single APP homologue called APP Like (APPL). Previous studies have provided evidence for the implication of APPL in neuronal wiring and axonal growth through the Wnt signaling pathway during development. However, like APP, APPL continues to be expressed in all neurons of the adult brain where its functions and their molecular and cellular underpinnings are unknown. We report that APPL loss of function (LOF) results in the dysregulation of endolysosomal function in neurons, with a notable enlargement of early endosomal compartments followed by neuronal cell death and the accumulation of dead neurons in the brain during a critical period at a young age. These defects can be rescued by reduction in the levels of the early endosomal regulator Rab5, indicating a causal role of endosomal function for cell death. Finally, we show that the secreted extracellular domain of APPL interacts with glia and regulates the size of their endosomes, the expression of the Draper engulfment receptor, and the clearance of neuronal debris in an axotomy model. We propose that APP proteins represent a novel family of neuroglial signaling factors required for adult brain homeostasis.
The actions of others act as a pseudo-reward to drive imitation in the context of social reinforcement learning
Venue: PLoS biology

While there is no doubt that social signals affect human reinforcement learning, there is still no consensus about how this process is computationally implemented. To address this issue, we compared three psychologically plausible hypotheses about the algorithmic implementation of imitation in reinforcement learning. The first hypothesis, decision biasing (DB), postulates that imitation consists in transiently biasing the learner’s action selection without affecting their value function. According to the second hypothesis, model-based imitation (MB), the learner infers the demonstrator’s value function through inverse reinforcement learning and uses it to bias action selection. Finally, according to the third hypothesis, value shaping (VS), the demonstrator’s actions directly affect the learner’s value function. We tested these three hypotheses in 2 experiments (N = 24 and N = 44) featuring a new variant of a social reinforcement learning task. We show through model comparison and model simulation that VS provides the best explanation of learner’s behavior. Results replicated in a third independent experiment featuring a larger cohort and a different design (N = 302). In our experiments, we also manipulated the quality of the demonstrators’ choices and found that learners were able to adapt their imitation rate, so that only skilled demonstrators were imitated. We proposed and tested an efficient meta-learning process to account for this effect, where imitation is regulated by the agreement between the learner and the demonstrator. In sum, our findings provide new insights and perspectives on the computational mechanisms underlying adaptive imitation in human reinforcement learning.
Diagnosis of latent tuberculosis infection is associated with reduced HIV viral load and lower risk for opportunistic infections in people living with HIV
Venue: PLoS biology

Approximately 28% of the human population have been exposed to Mycobacterium tuberculosis (MTB), with the overwhelming majority of infected individuals not developing disease (latent TB infection (LTBI)). While it is known that uncontrolled HIV infection is a major risk factor for the development of TB, the effect of underlying LTBI on HIV disease progression is less well characterized, in part because longitudinal data are lacking. We sorted all participants of the Swiss HIV Cohort Study (SHCS) with at least 1 documented MTB test into one of the 3 groups: MTB uninfected, LTBI, or active TB. To detect differences in the HIV set point viral load (SPVL), linear regression was used; the frequency of the most common opportunistic infections (OIs) in the SHCS between MTB uninfected patients, patients with LTBI, and patients with active TB were compared using logistic regression and time-to-event analyses. In adjusted models, we corrected for baseline demographic characteristics, i.e., HIV transmission risk group and gender, geographic region, year of HIV diagnosis, and CD4 nadir. A total of 13,943 SHCS patients had at least 1 MTB test documented, of whom 840 (6.0%) had LTBI and 770 (5.5%) developed active TB. Compared to MTB uninfected patients, LTBI was associated with a 0.24 decreased log HIV SPVL in the adjusted model (p < 0.0001). Patients with LTBI had lower odds of having candida stomatitis (adjusted odds ratio (OR) = 0.68, p = 0.0035) and oral hairy leukoplakia (adjusted OR = 0.67, p = 0.033) when compared to MTB uninfected patients. The association of LTBI with a reduced HIV set point virus load and fewer unrelated infections in HIV/TB coinfected patients suggests a more complex interaction between LTBI and HIV than previously assumed.
Generalizable brain network markers of major depressive disorder across multiple imaging sites
Venue: PLoS biology

Many studies have highlighted the difficulty inherent to the clinical application of fundamental neuroscience knowledge based on machine learning techniques. It is difficult to generalize machine learning brain markers to the data acquired from independent imaging sites, mainly due to large site differences in functional magnetic resonance imaging. We address the difficulty of finding a generalizable marker of major depressive disorder (MDD) that would distinguish patients from healthy controls based on resting-state functional connectivity patterns. For the discovery dataset with 713 participants from 4 imaging sites, we removed site differences using our recently developed harmonization method and developed a machine learning MDD classifier. The classifier achieved an approximately 70% generalization accuracy for an independent validation dataset with 521 participants from 5 different imaging sites. The successful generalization to a perfectly independent dataset acquired from multiple imaging sites is novel and ensures scientific reproducibility and clinical applicability.
Prior expectations evoke stimulus-specific activity in the deep layers of the primary visual cortex
Venue: PLoS biology

The way we perceive the world is strongly influenced by our expectations. In line with this, much recent research has revealed that prior expectations strongly modulate sensory processing. However, the neural circuitry through which the brain integrates external sensory inputs with internal expectation signals remains unknown. In order to understand the computational architecture of the cortex, we need to investigate the way these signals flow through the cortical layers. This is crucial because the different cortical layers have distinct intra- and interregional connectivity patterns, and therefore determining which layers are involved in a cortical computation can inform us on the sources and targets of these signals. Here, we used ultra-high field (7T) functional magnetic resonance imaging (fMRI) to reveal that prior expectations evoke stimulus-specific activity selectively in the deep layers of the primary visual cortex (V1). These findings are in line with predictive processing theories proposing that neurons in the deep cortical layers represent perceptual hypotheses and thereby shed light on the computational architecture of cortex.
Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia
Venue: PLoS biology

Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders.
Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing the Aldob/Akt/PP2A protein complex
Venue: PLoS biology

Loss of hepatic fructose-1, 6-bisphosphate aldolase B (Aldob) leads to a paradoxical up-regulation of glucose metabolism to favor hepatocellular carcinogenesis (HCC), but the upstream signaling events remain poorly defined. Akt is highly activated in HCC, and targeting Akt is being explored as a potential therapy for HCC. Herein, we demonstrate that Aldob suppresses Akt activity and tumor growth through a protein complex containing Aldob, Akt, and protein phosphatase 2A (PP2A), leading to inhibition of cell viability, cell cycle progression, glucose uptake, and metabolism. Interestingly, Aldob directly interacts with phosphorylated Akt (p-Akt) and promotes the recruitment of PP2A to dephosphorylate p-Akt, and this scaffolding effect of Aldob is independent of its enzymatic activity. Loss of Aldob or disruption of Aldob/Akt interaction in Aldob R304A mutant restores Akt activity and tumor-promoting effects. Consistently, Aldob and p-Akt expression are inversely correlated in human HCC tissues, and Aldob down-regulation coupled with p-Akt up-regulation predicts a poor prognosis for HCC. We have further discovered that Akt inhibition or a specific small-molecule activator of PP2A (SMAP) efficiently attenuates HCC tumorigenesis in xenograft mouse models. Our work reveals a novel nonenzymatic role of Aldob in negative regulation of Akt activation, suggesting that directly inhibiting Akt activity or through reactivating PP2A may be a potential therapeutic approach for HCC treatment.
Primate phylogenomics uncovers multiple rapid radiations and ancient interspecific introgression
Venue: PLoS biology

Our understanding of the evolutionary history of primates is undergoing continual revision due to ongoing genome sequencing efforts. Bolstered by growing fossil evidence, these data have led to increased acceptance of once controversial hypotheses regarding phylogenetic relationships, hybridization and introgression, and the biogeographical history of primate groups. Among these findings is a pattern of recent introgression between species within all major primate groups examined to date, though little is known about introgression deeper in time. To address this and other phylogenetic questions, here, we present new reference genome assemblies for 3 Old World monkey (OWM) species: Colobus angolensis ssp. palliatus (the black and white colobus), Macaca nemestrina (southern pig-tailed macaque), and Mandrillus leucophaeus (the drill). We combine these data with 23 additional primate genomes to estimate both the species tree and individual gene trees using thousands of loci. While our species tree is largely consistent with previous phylogenetic hypotheses, the gene trees reveal high levels of genealogical discordance associated with multiple primate radiations. We use strongly asymmetric patterns of gene tree discordance around specific branches to identify multiple instances of introgression between ancestral primate lineages. In addition, we exploit recent fossil evidence to perform fossil-calibrated molecular dating analyses across the tree. Taken together, our genome-wide data help to resolve multiple contentious sets of relationships among primates, while also providing insight into the biological processes and technical artifacts that led to the disagreements in the first place.
Subpopulations of sensorless bacteria drive fitness in fluctuating environments
Venue: PLoS biology

Populations of bacteria often undergo a lag in growth when switching conditions. Because growth lags can be large compared to typical doubling times, variations in growth lag are an important but often overlooked component of bacterial fitness in fluctuating environments. We here explore how growth lag variation is determined for the archetypical switch from glucose to lactose as a carbon source in Escherichia coli. First, we show that single-cell lags are bimodally distributed and controlled by a single-molecule trigger. That is, gene expression noise causes the population before the switch to divide into subpopulations with zero and nonzero lac operon expression. While “sensorless” cells with zero preexisting lac expression at the switch have long lags because they are unable to sense the lactose signal, any nonzero lac operon expression suffices to ensure a short lag. Second, we show that the growth lag at the population level depends crucially on the fraction of sensorless cells and that this fraction in turn depends sensitively on the growth condition before the switch. Consequently, even small changes in basal expression can significantly affect the fraction of sensorless cells, thereby population lags and fitness under switching conditions, and may thus be subject to significant natural selection. Indeed, we show that condition-dependent population lags vary across wild E. coli isolates. Since many sensory genes are naturally low expressed in conditions where their inducer is not present, bimodal responses due to subpopulations of sensorless cells may be a general mechanism inducing phenotypic heterogeneity and controlling population lags in switching environments. This mechanism also illustrates how gene expression noise can turn even a simple sensory gene circuit into a bet hedging module and underlines the profound role of gene expression noise in regulatory responses.
Transmembrane tumor necrosis factor alpha attenuates pressure-overload cardiac hypertrophy via tumor necrosis factor receptor 2
Venue: PLoS biology

Tumor necrosis factor-alpha (TNF-α) plays an important pathogenic role in cardiac hypertrophy and heart failure (HF); however, anti-TNF is paradoxically negative in clinical trials and even worsens HF, indicating a possible protective role of TNF-α in HF. TNF-α exists in transmembrane (tmTNF-α) and soluble (sTNF-α) forms. Herein, we found that TNF receptor 1 (TNFR1) knockout (KO) or knockdown (KD) by short hairpin RNA or small interfering RNA (siRNA) significantly alleviated cardiac hypertrophy, heart dysfunction, fibrosis, and inflammation with increased tmTNF-α expression, whereas TNFR2 KO or KD exacerbated the pathological phenomena with increased sTNF-α secretion in transverse aortic constriction (TAC)- and isoproterenol (ISO)-induced cardiac hypertrophy in vivo and in vitro, respectively, indicating the beneficial effects of TNFR2 associated with tmTNF-α. Suppressing TNF-α converting enzyme by TNF-α Protease Inhibitor-1 (TAPI-1) to increase endogenous tmTNF-α expression significantly alleviated TAC-induced cardiac hypertrophy. Importantly, direct addition of exogenous tmTNF-α into cardiomyocytes in vitro significantly reduced ISO-induced cardiac hypertrophy and transcription of the pro-inflammatory cytokines and induced proliferation. The beneficial effects of tmTNF-α were completely blocked by TNFR2 KD in H9C2 cells and TNFR2 KO in primary myocardial cells. Furthermore, we demonstrated that tmTNF-α displayed antihypertrophic and anti-inflammatory effects by activating the AKT pathway and inhibiting the nuclear factor (NF)-κB pathway via TNFR2. Our data suggest that tmTNF-α exerts cardioprotective effects via TNFR2. Specific targeting of tmTNF-α processing, rather than anti-TNF therapy, may be more useful for the treatment of hypertrophy and HF.