nils-herrmann/clean_scirepeval huggingface dataset:
Kif13b Regulates PNS and CNS Myelination through the Dlg1 Scaffold
Venue: PLoS biology

Microtubule-based kinesin motors have many cellular functions, including the transport of a variety of cargos. However, unconventional roles have recently emerged, and kinesins have also been reported to act as scaffolding proteins and signaling molecules. In this work, we further extend the notion of unconventional functions for kinesin motor proteins, and we propose that Kif13b kinesin acts as a signaling molecule regulating peripheral nervous system (PNS) and central nervous system (CNS) myelination. In this process, positive and negative signals must be tightly coordinated in time and space to orchestrate myelin biogenesis. Here, we report that in Schwann cells Kif13b positively regulates myelination by promoting p38γ mitogen-activated protein kinase (MAPK)-mediated phosphorylation and ubiquitination of Discs large 1 (Dlg1), a known brake on myelination, which downregulates the phosphatidylinositol 3-kinase (PI3K)/v-AKT murine thymoma viral oncogene homolog (AKT) pathway. Interestingly, Kif13b also negatively regulates Dlg1 stability in oligodendrocytes, in which Dlg1, in contrast to Schwann cells, enhances AKT activation and promotes myelination. Thus, our data indicate that Kif13b is a negative regulator of CNS myelination. In summary, we propose a novel function for the Kif13b kinesin in glial cells as a key component of the PI3K/AKT signaling pathway, which controls myelination in both PNS and CNS.
Time Slices: What Is the Duration of a Percept?
Venue: PLoS biology

We experience the world as a seamless stream of percepts. However, intriguing illusions and recent experiments suggest that the world is not continuously translated into conscious perception. Instead, perception seems to operate in a discrete manner, just like movies appear continuous although they consist of discrete images. To explain how the temporal resolution of human vision can be fast compared to sluggish conscious perception, we propose a novel conceptual framework in which features of objects, such as their color, are quasi-continuously and unconsciously analyzed with high temporal resolution. Like other features, temporal features, such as duration, are coded as quantitative labels. When unconscious processing is “completed,” all features are simultaneously rendered conscious at discrete moments in time, sometimes even hundreds of milliseconds after stimuli were presented.
Gauging the Purported Costs of Public Data Archiving for Long-Term Population Studies
Venue: PLoS biology

It was recently proposed that long-term population studies be exempted from the expectation that authors publicly archive the primary data underlying published articles. Such studies are valuable to many areas of ecological and evolutionary biological research, and multiple risks to their viability were anticipated as a result of public data archiving (PDA), ultimately all stemming from independent reuse of archived data. However, empirical assessment was missing, making it difficult to determine whether such fears are realistic. I addressed this by surveying data packages from long-term population studies archived in the Dryad Digital Repository. I found no evidence that PDA results in reuse of data by independent parties, suggesting the purported costs of PDA for long-term population studies have been overstated.
Reinventing Biostatistics Education for Basic Scientists
Venue: PLoS biology

Numerous studies demonstrating that statistical errors are common in basic science publications have led to calls to improve statistical training for basic scientists. In this article, we sought to evaluate statistical requirements for PhD training and to identify opportunities for improving biostatistics education in the basic sciences. We provide recommendations for improving statistics training for basic biomedical scientists, including: 1. Encouraging departments to require statistics training, 2. Tailoring coursework to the students’ fields of research, and 3. Developing tools and strategies to promote education and dissemination of statistical knowledge. We also provide a list of statistical considerations that should be addressed in statistics education for basic scientists.
Correction: The Grand Convergence: Closing the Divide between Public Health Funding and Global Health Needs
Venue: PLoS biology

This article was republished on March 15, 2016, to correct errors in the article layout that were introduced during the typesetting process. Specifically, the abstract should have only contained a single paragraph, however the first two paragraphs of the main article text were also included in this. The publisher apologizes for the errors. Please download this article again to view the correct version. The originally published, uncorrected article and the republished, corrected articles are provided here for reference.
Excessive Osteocytic Fgf23 Secretion Contributes to Pyrophosphate Accumulation and Mineralization Defect in Hyp Mice
Venue: PLoS biology

X-linked hypophosphatemia (XLH) is the most frequent form of inherited rickets in humans caused by mutations in the phosphate-regulating gene with homologies to endopeptidases on the X-chromosome (PHEX). Hyp mice, a murine homologue of XLH, are characterized by hypophosphatemia, inappropriately low serum vitamin D levels, increased serum fibroblast growth factor-23 (Fgf23), and osteomalacia. Although Fgf23 is known to be responsible for hypophosphatemia and reduced vitamin D hormone levels in Hyp mice, its putative role as an auto-/paracrine osteomalacia-causing factor has not been explored. We recently reported that Fgf23 is a suppressor of tissue nonspecific alkaline phosphatase (Tnap) transcription via FGF receptor-3 (FGFR3) signaling, leading to inhibition of mineralization through accumulation of the TNAP substrate pyrophosphate. Here, we report that the pyrophosphate concentration is increased in Hyp bones, and that Tnap expression is decreased in Hyp-derived osteocyte-like cells but not in Hyp-derived osteoblasts ex vivo and in vitro. In situ mRNA expression profiling in bone cryosections revealed a ~70-fold up-regulation of Fgfr3 mRNA in osteocytes versus osteoblasts of Hyp mice. In addition, we show that blocking of increased Fgf23-FGFR3 signaling with anti-Fgf23 antibodies or an FGFR3 inhibitor partially restored the suppression of Tnap expression, phosphate production, and mineralization, and decreased pyrophosphate concentration in Hyp-derived osteocyte-like cells in vitro. In vivo, bone-specific deletion of Fgf23 in Hyp mice rescued the suppressed TNAP activity in osteocytes of Hyp mice. Moreover, treatment of wild-type osteoblasts or mice with recombinant FGF23 suppressed Tnap mRNA expression and increased pyrophosphate concentrations in the culture medium and in bone, respectively. In conclusion, we found that the cell autonomous increase in Fgf23 secretion in Hyp osteocytes drives the accumulation of pyrophosphate through auto-/paracrine suppression of TNAP. Hence, we have identified a novel mechanism contributing to the mineralization defect in Hyp mice.
NREM2 and Sleep Spindles Are Instrumental to the Consolidation of Motor Sequence Memories
Venue: PLoS biology

Although numerous studies have convincingly demonstrated that sleep plays a critical role in motor sequence learning (MSL) consolidation, the specific contribution of the different sleep stages in this type of memory consolidation is still contentious. To probe the role of stage 2 non-REM sleep (NREM2) in this process, we used a conditioning protocol in three different groups of participants who either received an odor during initial training on a motor sequence learning task and were re-exposed to this odor during different sleep stages of the post-training night (i.e., NREM2 sleep [Cond-NREM2], REM sleep [Cond-REM], or were not conditioned during learning but exposed to the odor during NREM2 [NoCond]). Results show that the Cond-NREM2 group had significantly higher gains in performance at retest than both the Cond-REM and NoCond groups. Also, only the Cond-NREM2 group yielded significant changes in sleep spindle characteristics during cueing. Finally, we found that a change in frequency of sleep spindles during cued-memory reactivation mediated the relationship between the experimental groups and gains in performance the next day. These findings strongly suggest that cued-memory reactivation during NREM2 sleep triggers an increase in sleep spindle activity that is then related to the consolidation of motor sequence memories.
Dredging in the Spratly Islands: Gaining Land but Losing Reefs
Venue: PLoS biology

Coral reefs on remote islands and atolls are less exposed to direct human stressors but are becoming increasingly vulnerable because of their development for geopolitical and military purposes. Here we document dredging and filling activities by countries in the South China Sea, where building new islands and channels on atolls is leading to considerable losses of, and perhaps irreversible damages to, unique coral reef ecosystems. Preventing similar damage across other reefs in the region necessitates the urgent development of cooperative management of disputed territories in the South China Sea. We suggest using the Antarctic Treaty as a positive precedent for such international cooperation.
Epidermal Growth Factor Receptor-Dependent Mutual Amplification between Netrin-1 and the Hepatitis C Virus
Venue: PLoS biology

Hepatitis C virus (HCV) is an oncogenic virus associated with the onset of hepatocellular carcinoma (HCC). The present study investigated the possible link between HCV infection and Netrin-1, a ligand for dependence receptors that sustains tumorigenesis, in particular in inflammation-associated tumors. We show that Netrin-1 expression is significantly elevated in HCV+ liver biopsies compared to hepatitis B virus (HBV+) and uninfected samples. Furthermore, Netrin-1 was upregulated in all histological stages of HCV+ hepatic lesions, from minimal liver fibrosis to cirrhosis and HCC, compared to histologically matched HCV- tissues. Both cirrhosis and HCV contributed to the induction of Netrin-1 expression, whereas anti-HCV treatment resulted in a reduction of Netrin-1 expression. In vitro, HCV increased the level and translation of Netrin-1 in a NS5A-La-related protein 1 (LARP1)-dependent fashion. Knockdown and forced expression experiments identified the receptor uncoordinated receptor-5 (UNC5A) as an antagonist of the Netrin-1 signal, though it did not affect the death of HCV-infected cells. Netrin-1 enhanced infectivity of HCV particles and promoted viral entry by increasing the activation and decreasing the recycling of the epidermal growth factor receptor (EGFR), a protein that is dysregulated in HCC. Netrin-1 and HCV are, therefore, reciprocal inducers in vitro and in patients, as seen from the increase in viral morphogenesis and viral entry, both phenomena converging toward an increase in the level of infectivity of HCV virions. This functional association involving a cancer-related virus and Netrin-1 argues for evaluating the implication of UNC5 receptor ligands in other oncogenic microbial species.
Remotely Sensed High-Resolution Global Cloud Dynamics for Predicting Ecosystem and Biodiversity Distributions
Venue: PLoS biology

Cloud cover can influence numerous important ecological processes, including reproduction, growth, survival, and behavior, yet our assessment of its importance at the appropriate spatial scales has remained remarkably limited. If captured over a large extent yet at sufficiently fine spatial grain, cloud cover dynamics may provide key information for delineating a variety of habitat types and predicting species distributions. Here, we develop new near-global, fine-grain (≈1 km) monthly cloud frequencies from 15 y of twice-daily Moderate Resolution Imaging Spectroradiometer (MODIS) satellite images that expose spatiotemporal cloud cover dynamics of previously undocumented global complexity. We demonstrate that cloud cover varies strongly in its geographic heterogeneity and that the direct, observation-based nature of cloud-derived metrics can improve predictions of habitats, ecosystem, and species distributions with reduced spatial autocorrelation compared to commonly used interpolated climate data. These findings support the fundamental role of remote sensing as an effective lens through which to understand and globally monitor the fine-grain spatial variability of key biodiversity and ecosystem properties.
Crystal Structure of an Ammonia-Permeable Aquaporin
Venue: PLoS biology

Aquaporins of the TIP subfamily (Tonoplast Intrinsic Proteins) have been suggested to facilitate permeation of water and ammonia across the vacuolar membrane of plants, allowing the vacuole to efficiently sequester ammonium ions and counteract cytosolic fluctuations of ammonia. Here, we report the structure determined at 1.18 Å resolution from twinned crystals of Arabidopsis thaliana aquaporin AtTIP2;1 and confirm water and ammonia permeability of the purified protein reconstituted in proteoliposomes as further substantiated by molecular dynamics simulations. The structure of AtTIP2;1 reveals an extended selectivity filter with the conserved arginine of the filter adopting a unique unpredicted position. The relatively wide pore and the polar nature of the selectivity filter clarify the ammonia permeability. By mutational studies, we show that the identified determinants in the extended selectivity filter region are sufficient to convert a strictly water-specific human aquaporin into an AtTIP2;1-like ammonia channel. A flexible histidine and a novel water-filled side pore are speculated to deprotonate ammonium ions, thereby possibly increasing permeation of ammonia. The molecular understanding of how aquaporins facilitate ammonia flux across membranes could potentially be used to modulate ammonia losses over the plasma membrane to the atmosphere, e.g., during photorespiration, and thereby to modify the nitrogen use efficiency of plants.
Modulation of Cortical Oscillations by Low-Frequency Direct Cortical Stimulation Is State-Dependent
Venue: PLoS biology

Cortical oscillations play a fundamental role in organizing large-scale functional brain networks. Noninvasive brain stimulation with temporally patterned waveforms such as repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) have been proposed to modulate these oscillations. Thus, these stimulation modalities represent promising new approaches for the treatment of psychiatric illnesses in which these oscillations are impaired. However, the mechanism by which periodic brain stimulation alters endogenous oscillation dynamics is debated and appears to depend on brain state. Here, we demonstrate with a static model and a neural oscillator model that recurrent excitation in the thalamo-cortical circuit, together with recruitment of cortico-cortical connections, can explain the enhancement of oscillations by brain stimulation as a function of brain state. We then performed concurrent invasive recording and stimulation of the human cortical surface to elucidate the response of cortical oscillations to periodic stimulation and support the findings from the computational models. We found that (1) stimulation enhanced the targeted oscillation power, (2) this enhancement outlasted stimulation, and (3) the effect of stimulation depended on behavioral state. Together, our results show successful target engagement of oscillations by periodic brain stimulation and highlight the role of nonlinear interaction between endogenous network oscillations and stimulation. These mechanistic insights will contribute to the design of adaptive, more targeted stimulation paradigms.
Conservation Research Is Not Happening Where It Is Most Needed
Venue: PLoS biology

Target 19, set by the Convention on Biological Diversity, seeks to improve the knowledge, science base, and technologies relating to biodiversity. We will fail to achieve this target unless prolific biases in the field of conservation science are addressed. We reveal that comparatively less research is undertaken in the world’s most biodiverse countries, the science conducted in these countries is often not led by researchers based in-country, and these scientists are also underrepresented in important international fora. Mitigating these biases requires wide-ranging solutions: reforming open access publishing policies, enhancing science communication strategies, changing author attribution practices, improving representation in international processes, and strengthening infrastructure and human capacity for research in countries where it is most needed.
The Effects of Context and Attention on Spiking Activity in Human Early Visual Cortex
Venue: PLoS biology

Here we report the first quantitative analysis of spiking activity in human early visual cortex. We recorded multi-unit activity from two electrodes in area V2/V3 of a human patient implanted with depth electrodes as part of her treatment for epilepsy. We observed well-localized multi-unit receptive fields with tunings for contrast, orientation, spatial frequency, and size, similar to those reported in the macaque. We also observed pronounced gamma oscillations in the local-field potential that could be used to estimate the underlying spiking response properties. Spiking responses were modulated by visual context and attention. We observed orientation-tuned surround suppression: responses were suppressed by image regions with a uniform orientation and enhanced by orientation contrast. Additionally, responses were enhanced on regions that perceptually segregated from the background, indicating that neurons in the human visual cortex are sensitive to figure-ground structure. Spiking responses were also modulated by object-based attention. When the patient mentally traced a curve through the neurons’ receptive fields, the accompanying shift of attention enhanced neuronal activity. These results demonstrate that the tuning properties of cells in the human early visual cortex are similar to those in the macaque and that responses can be modulated by both contextual factors and behavioral relevance. Our results, therefore, imply that the macaque visual system is an excellent model for the human visual cortex.
Low Genetic Quality Alters Key Dimensions of the Mutational Spectrum
Venue: PLoS biology

Mutations affect individual health, population persistence, adaptation, diversification, and genome evolution. There is evidence that the mutation rate varies among genotypes, but the causes of this variation are poorly understood. Here, we link differences in genetic quality with variation in spontaneous mutation in a Drosophila mutation accumulation experiment. We find that chromosomes maintained in low-quality genetic backgrounds experience a higher rate of indel mutation and a lower rate of gene conversion in a manner consistent with condition-based differences in the mechanisms used to repair DNA double strand breaks. These aspects of the mutational spectrum were also associated with body mass, suggesting that the effect of genetic quality on DNA repair was mediated by overall condition, and providing a mechanistic explanation for the differences in mutational fitness decline among these genotypes. The rate and spectrum of substitutions was unaffected by genetic quality, but we find variation in the probability of substitutions and indels with respect to several aspects of local sequence context, particularly GC content, with implications for models of molecular evolution and genome scans for signs of selection. Our finding that the chances of mutation depend on genetic context and overall condition has important implications for how sequences evolve, the risk of extinction, and human health.
Hemotin, a Regulator of Phagocytosis Encoded by a Small ORF and Conserved across Metazoans
Venue: PLoS biology

Translation of hundreds of small ORFs (smORFs) of less than 100 amino acids has recently been revealed in vertebrates and Drosophila. Some of these peptides have essential and conserved cellular functions. In Drosophila, we have predicted a particular smORF class encoding ~80 aa hydrophobic peptides, which may function in membranes and cell organelles. Here, we characterise hemotin, a gene encoding an 88aa transmembrane smORF peptide localised to early endosomes in Drosophila macrophages. hemotin regulates endosomal maturation during phagocytosis by repressing the cooperation of 14-3-3ζ with specific phosphatidylinositol (PI) enzymes. hemotin mutants accumulate undigested phagocytic material inside enlarged endo-lysosomes and as a result, hemotin mutants have reduced ability to fight bacteria, and hence, have severely reduced life span and resistance to infections. We identify Stannin, a peptide involved in organometallic toxicity, as the Hemotin functional homologue in vertebrates, showing that this novel regulator of phagocytic processing is widely conserved, emphasizing the significance of smORF peptides in cell biology and disease.
Correction: Hypoxia-Inducible Factor Directs POMC Gene to Mediate Hypothalamic Glucose Sensing and Energy Balance Regulation
Venue: PLoS biology

It has come to the authors' attention that the HIF2α blot in Fig 6A and the β-actin blot in Fig 3B were inadvertently duplicated in Fig 5A and S6C Fig, respectively. The authors provided original blots and records for the editors to verify and have now reproduced these figures with the correct data. Revised versions of Fig 5 and S6 Fig are provided here. 
 
 
 
Fig 5 
 
Effect of AMPK in glucose-mediated activation of hypothalamic HIF.
Transgenerational Epigenetic Contributions to Stress Responses: Fact or Fiction?
Venue: PLoS biology

There has been increasing interest in the possibility that behavioral experience—in particular, exposure to stress—can be passed on to subsequent generations through heritable epigenetic modifications. The possibility remains highly controversial, however, reflecting the lack of standardized definitions of epigenetics and the limited empirical support for potential mechanisms of transgenerational epigenetic inheritance. Nonetheless, growing evidence supports a role for epigenetic regulation as a key mechanism underlying lifelong regulation of gene expression that mediates stress vulnerability. This Perspective provides an overview of the multiple meanings of the term epigenetic, discusses the challenges of studying epigenetic contributions to stress susceptibility—and the experimental evidence for and against the existence of such mechanisms—and outlines steps required for future investigations.