Miracle-dz/UniFAR-FTUs huggingface dataset:
Predicting the Disposition of the Antimalarial Drug Artesunate and Its Active Metabolite Dihydroartemisinin Using Physiologically Based Pharmacokinetic Modeling

Artemisinin-based combination therapies (ACTs) have proven to be effective in helping to combat the global malaria epidemic. To optimally apply these drugs, information about their tissue-specific disposition is required, and one approach to predict these pharmacokinetic characteristics is physiologically based pharmacokinetic (PBPK) modeling. ABSTRACT Artemisinin-based combination therapies (ACTs) have proven to be effective in helping to combat the global malaria epidemic. To optimally apply these drugs, information about their tissue-specific disposition is required, and one approach to predict these pharmacokinetic characteristics is physiologically based pharmacokinetic (PBPK) modeling. In this study, a whole-body PBPK model was developed to simulate the time-dependent tissue concentrations of artesunate (AS) and its active metabolite, dihydroartemisinin (DHA). The model was developed for both rats and humans and incorporated drug metabolism of the parent compound and major metabolite. Model calibration was conducted using data from the literature in a Bayesian framework, and model verification was assessed using separate sets of data. Results showed good agreement between model predictions and the validation data, demonstrating the capability of the model in predicting the blood, plasma, and tissue pharmacokinetics of AS and DHA. It is expected that such a tool will be useful in characterizing the disposition of these chemicals and ultimately improve dosing regimens by enabling a quantitative assessment of the tissue-specific drug levels critical in the evaluation of efficacy and toxicity.
Sexual selection theory meets disease vector control: Testing harmonic convergence as a “good genes” signal in Aedes aegypti mosquitoes

The mosquito Aedes aegypti is a medically important, globally distributed vector of the viruses that cause dengue, yellow fever, chikungunya, and Zika. Although reproduction and mate choice are key components of vector population dynamics and control, our understanding of the mechanisms of sexual selection in mosquitoes remains poor. In “good genes” models of sexual selection, females use male cues as an indicator of both mate and offspring inherent genetic quality. Recent studies in Ae. aegypti provide evidence that male wingbeat acoustics signal aspects of offspring quality and performance during mate selection in a process known as harmonic convergence. However, the extent to which harmonic convergence may signal overall inherent quality of mates and their offspring remains unknown. To examine this, we measured the potential acoustic signaling and heritability of a broad panel of parent and offspring fitness traits in two generations of field-derived Ae. aegypti originating from dengue endemic field sites in Thailand. Our data show that in this population of mosquitoes, harmonic convergence does not signal male fertility, female fecundity, and male flight performance traits, which despite displaying robust variability in both parents and their offspring were only weakly heritable. Together with previous work, our findings suggest that vector reproductive control programs should treat harmonic convergence as an indicator of some, but not all aspects of inherent quality, and that multiple forms of sexual selection are likely at play in Ae. aegypti in a trait, population, and environment dependent manner.
Predicting COVID-19 Severity with a Specific Nucleocapsid Antibody plus Disease Risk Factor Score

The COVID-19 pandemic has resulted in over two million deaths worldwide. Despite efforts to fight the virus, the disease continues to overwhelm hospitals with severely ill patients. ABSTRACT Effective methods for predicting COVID-19 disease trajectories are urgently needed. Here, enzyme-linked immunosorbent assay (ELISA) and coronavirus antigen microarray (COVAM) analysis mapped antibody epitopes in the plasma of COVID-19 patients (n = 86) experiencing a wide range of disease states. The experiments identified antibodies to a 21-residue epitope from nucleocapsid (termed Ep9) associated with severe disease, including admission to the intensive care unit (ICU), requirement for ventilators, or death. Importantly, anti-Ep9 antibodies can be detected within 6 days post-symptom onset and sometimes within 1 day. Furthermore, anti-Ep9 antibodies correlate with various comorbidities and hallmarks of immune hyperactivity. We introduce a simple-to-calculate, disease risk factor score to quantitate each patient’s comorbidities and age. For patients with anti-Ep9 antibodies, scores above 3.0 predict more severe disease outcomes with a 13.42 likelihood ratio (96.7% specificity). The results lay the groundwork for a new type of COVID-19 prognostic to allow early identification and triage of high-risk patients. Such information could guide more effective therapeutic intervention. IMPORTANCE The COVID-19 pandemic has resulted in over two million deaths worldwide. Despite efforts to fight the virus, the disease continues to overwhelm hospitals with severely ill patients. Diagnosis of COVID-19 is readily accomplished through a multitude of reliable testing platforms; however, prognostic prediction remains elusive. To this end, we identified a short epitope from the SARS-CoV-2 nucleocapsid protein and also a disease risk factor score based upon comorbidities and age. The presence of antibodies specifically binding to this epitope plus a score cutoff can predict severe COVID-19 outcomes with 96.7% specificity.
Neural basis of opioid-induced respiratory depression and its rescue

Significance Opioid-induced respiratory depression (OIRD) is the direct cause of death from opioid overdose, which accounts for the current global opioid crisis. Here, we report that neurons expressing the μ-opioid receptors in the lateral parabrachial nucleus of the pontine respiratory group are necessary and sufficient for the pathogenesis of OIRD. Activating these neurons through endogenous or artificial G protein–coupled receptor signaling pathways rescues OIRD in intact mice, suggesting its therapeutic utility in OIRD patients. Opioid-induced respiratory depression (OIRD) causes death following an opioid overdose, yet the neurobiological mechanisms of this process are not well understood. Here, we show that neurons within the lateral parabrachial nucleus that express the µ-opioid receptor (PBLOprm1 neurons) are involved in OIRD pathogenesis. PBLOprm1 neuronal activity is tightly correlated with respiratory rate, and this correlation is abolished following morphine injection. Chemogenetic inactivation of PBLOprm1 neurons mimics OIRD in mice, whereas their chemogenetic activation following morphine injection rescues respiratory rhythms to baseline levels. We identified several excitatory G protein–coupled receptors expressed by PBLOprm1 neurons and show that agonists for these receptors restore breathing rates in mice experiencing OIRD. Thus, PBLOprm1 neurons are critical for OIRD pathogenesis, providing a promising therapeutic target for treating OIRD in patients.
Novel enzyme for dimethyl sulfide-releasing in bacteria reveals a missing route in the marine sulfur cycle

Dimethylsulfoniopropionate (DMSP) is an abundant and ubiquitous organosulfur molecule and plays important roles in the global sulfur cycle. Cleavage of DMSP produces volatile dimethyl sulfide (DMS), which has impacts on the global climate. Multiple pathways for DMSP catabolism have been identified. Here we identified yet another novel pathway, the ATP DMSP lysis pathway. The key enzyme, AcoD, is an ATP-dependent DMSP lyase. AcoD belongs to the acyl-CoA synthetase superfamily, which is totally different from other DMSP lyases, showing a new evolution route. AcoD catalyses the conversion of DMSP to DMS by a two-step reaction: the ligation of DMSP with CoA to form the intermediate DMSP-CoA, which is then cleaved to DMS and acryloyl-CoA. The novel catalytic mechanism was elucidated by structural and biochemical analyses. AcoD is widely distributed in many bacterial lineages including Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria and Firmicutes, revealing this new pathway plays important roles in global DMSP/DMS cycles.
Separable neural mechanisms support intentional forgetting and thought substitution

Psychological and neuroscientific experiments have established that people can intentionally forget information via different strategies: direct suppression and thought substitution. However, few studies have directly compared the effectiveness of these strategies in forgetting specific items, and it remains an open question if the neural mechanisms supporting these strategies differ. Here, we developed a novel item-method directed forgetting paradigm with Remember, Forget, and Imagine cues, and recorded EEG to directly compare these strategies. Behaviorally, Forget and Imagine cues produced similar forgetting compared to Remember cues, but through separable neural processes; Forget cues elicited frontal oscillatory power changes that were predictive of future forgetting, whereas item-cue representational similarity was predictive of later accuracy for Imagine cues. These results suggest that both strategies can lead to intentional forgetting, but directed forgetting may rely on frontally-mediated suppression, while thought substitution may lead to contextual shifting, impairing successful retrieval.
An Eutherian-Specific microRNA Controls the Translation of Satb2 in a Model of Cortical Differentiation

Cerebral cortical development is controlled by key transcription factors that specify the neuronal identities in the different cortical layers. These transcription factors are crucial for the identity of the different neurons, but the mechanisms controlling their expression in distinct cells are only partially known. Here we investigate the expression and stability of the mRNAs of Tbr1, Bcl11b, Fezf2, Satb2 and Cux1 in single developing mouse cortical cells. We focus on Satb2 and find that its mRNA expression occurs much earlier than its protein synthesis and in a set of cells broader than expected, suggesting an initially tight control of its translation, which is subsequently de-repressed at late developmental stages. Mechanistically, Satb2 3’UTR modulates protein translation of GFP reporters during mouse corticogenesis. By in vitro pull-down of Satb2 3’UTR-associated miRNAs, we select putative miRNAs responsible for SATB2 inhibition, focusing on those strongly expressed in early progenitor cells and reduced in late cells. miR-541, an Eutherian-specific miRNA, and miR-92a/b are the best candidates and their inactivation triggers robust and premature SATB2 translation in both mouse and human cortical cells. Our findings indicate that RNA interference plays a major role in the timing of cortical cell identity and may be part of the toolkit involved in specifying supra-granular projection neurons.
A comprehensive reference transcriptome resource for the Iberian ribbed newt Pleurodeles waltl, an emerging model for developmental and regeneration biology

Urodele amphibian newts have unique biological properties, notably including prominent regeneration ability. Iberian ribbed newt, Pleurodeles waltl, is a promising model newt along with the successful development of the easy breeding system and efficient transgenic and genome editing methods. However, genetic information of P. waltl was limited. In the present study, we conducted an intensive transcriptome analysis of P. waltl using RNA-sequencing to build gene models and annotate them. We generated 1.2 billion Illumina reads from a wide variety of samples across 11 different tissues and 9 time points during embryogenesis. They were assembled into 202,788 non-redundant contigs that appear to cover nearly complete (~98%) P. waltl protein-coding genes. Using the gene set as a reference, our gene network analysis identified regeneration-, developmental-stage-, and tissue-specific co-expressed gene modules. Ortholog analyses with other vertebrates revealed the gene repertoire evolution of amphibians which includes urodele-specific loss of bmp4 and duplications of wnt11b. Our transcriptome resource will enhance future research employing this emerging model animal for regeneration research as well as other areas such as developmental biology, stem cell biology, cancer research, ethology and toxico-genomics. These data are available via our portal website, iNewt (http://www.nibb.ac.jp/imori/main/).
COVID-19 Disease Map, a computational knowledge repository of SARS-CoV-2 virus-host interaction mechanisms

We hereby describe a large-scale community effort to build an open-access, interoperable, and computable repository of COVID-19 molecular mechanisms - the COVID-19 Disease Map. We discuss the tools, platforms, and guidelines necessary for the distributed development of its contents by a multi-faceted community of biocurators, domain experts, bioinformaticians, and computational biologists. We highlight the role of relevant databases and text mining approaches in enrichment and validation of the curated mechanisms. We describe the contents of the map and their relevance to the molecular pathophysiology of COVID-19 and the analytical and computational modelling approaches that can be applied to the contents of the COVID-19 Disease Map for mechanistic data interpretation and predictions. We conclude by demonstrating concrete applications of our work through several use cases.
Multiple holins contribute to extracellular DNA release in Pseudomonas aeruginosa biofilms

Bacterial biofilms are comprised of aggregates of cells encased within a matrix of extracellular polymeric substances (EPS). One key EPS component is extracellular DNA (eDNA), which acts as a ‘glue’, facilitating cell-cell and cell-substratum interactions. We have previously demonstrated that eDNA is produced in Pseudomonas aeruginosa biofilms via explosive cell lysis. This phenomenon involves a subset of the bacterial population explosively lysing, due to peptidoglycan degradation by the endolysin Lys. Here we demonstrate that in P. aeruginosa three holins, AlpB, CidA and Hol, are involved in Lys-mediated eDNA release within both submerged (hydrated) and interstitial (actively expanding) biofilms, albeit to different extents, depending upon the type of biofilm and the stage of biofilm development. We also demonstrate that eDNA release events determine the sites at which cells begin to cluster to initiate microcolony formation during the early stages of submerged biofilm development. Furthermore, our results show that sustained release of eDNA is required for cell cluster consolidation and subsequent microcolony development in submerged biofilms. Overall, this study adds to our understanding of how eDNA release is controlled temporally and spatially within P. aeruginosa biofilms.
Unsupervised Learning of Brain State Dynamics during Emotion Imagery using High-Density EEG

Here we assume that emotional states correspond to functional dynamic states of brain and body, and attempt to characterize the appearance of these states in high-density scalp electroencephalographic (EEG) recordings acquired from 31 participants during 1-2 hour sessions, each including fifteen 3-5 min periods of self-induced emotion imagination using the method of guided imagery. EEG offers an objective and high-resolution measurement of whatever portion of cortical electrical dynamics is resolvable from scalp recordings. Despite preliminary progress in EEG-based emotion decoding using supervised machine learning methods, few studies have applied data-driven, unsupervised decomposition approaches to investigate the underlying EEG dynamics by characterizing brain temporal dynamics during emotional experience. This study applies an unsupervised approach – adaptive mixture independent component analysis (adaptive mixture ICA, AMICA) that learns a set of ICA models each accounted for portions of a given multi-channel EEG recording. We demonstrate that 20-model AMICA decomposition can identify distinct EEG patterns or dynamic states active during each of the fifteen emotion-imagery periods. The transition in EEG patterns revealed the time-courses of brain-state dynamics during emotional imagery. These time-courses varied across emotions: “grief” and “happiness” showed more abrupt transitions while “contentment” was nearly indistinguishable from the preceding rest period. The spatial distributions of independent components (ICs) of the AMICA models showed higher similarity within-subject across emotions than within-emotion across subjects. No significant differences in IC distributions were found between positive and negative emotions. However, significant changes in IC distributions during emotional imagery compared to rest were identified in brain areas such as the left prefrontal cortex, the posterior cingulate cortex, the motor cortex, and the visual cortex. The study demonstrates the feasibility of AMICA in modeling high-density and nonstationary EEG and its utility in providing data-driven insights into brain state dynamics during self-paced emotional experiences, which have been difficult to measure. This approach can advance our understanding of highly dynamical emotional processes and improve the performance of EEG-based emotion decoding for affective computing and human-computer interaction.
Older eastern white pine trees and stands sequester carbon for many decades and maximize cumulative carbon

Pre-settlement New England was heavily forested, with some trees exceeding 2 m in diameter. New England’s forests have regrown since farm abandonment and represent what is arguably the most successful regional reforestation on record; the region has recently been identified as part of the “Global Safety Net. ” Remnants and groves of primary “old-growth” forest demonstrate that native tree species can live for hundreds of years and continue to add to the biomass and structural and ecological complexity of forests. Forests are an essential natural climate solution for accumulating and storing atmospheric CO2, and some studies emphasize young, fast-growing trees and forests whereas others highlight high carbon storage and accumulation rates in old trees and intact forests. To address this question directly within New England we leveraged long-term, accurate field measurements along with volume modeling of individual trees and intact stands of eastern white pines (Pinus strobus) and compared our results to models developed by the U.S. Forest Service. Our major findings complement, extend, and clarify previous findings and are three-fold: 1) intact eastern white pine forests continue to sequester carbon and store high cumulative carbon above ground; 2) large trees dominate above-ground carbon storage and can sequester significant amounts of carbon for hundreds of years; 3) productive pine stands can continue to sequester high amounts of carbon for well over 150 years. Because the next decades are critical in addressing the climate crisis, and the vast majority of New England forests are less than 100 years old, and can at least double their cumulative carbon, a major implication of this work is that maintaining and accumulating maximal carbon in existing forests – proforestation - is a powerful near-term regional climate solution. Furthermore, old and old-growth forests are rare, complex and highly dynamic and biodiverse, and dedication of some forests to proforestation will also protect natural selection, ecosystem integrity and full native biodiversity long-term. In sum, strategic policies that grow and protect existing forests in New England will optimize a proven, low cost, natural climate solution for meeting climate and biodiversity goals now and in the critical coming decades.
High-human acuity of speed asymmetry during walking

Despite its central role in the proper functioning of the motor system, sensation has been less studied than motor output in sensorimotor adaptation paradigms. This deficit is probably due to the difficulty of measuring sensation: while motor output has easily observable consequences, sensation is by definition an internal variable of the motor system. In this study we asked how well can subjects estimate relevant environmental changes inducing motor adaptation. We addressed this question in the context of walking on a split-belt treadmill, which allows subjects to experience distinct belt speeds for each leg. We used a two-alternative forced-choice perceptual task (2AFC) in which subjects report which belt they thought to be moving slower. We characterized baseline accuracy in this task for healthy human subjects, and found 75% accuracy for 75 mm/s speed differences. Additionally, we used a drift-diffusion model of the task that could account for both accuracy and reaction times. We conclude that 2AFC tasks can be used to probe subjects’ estimates of the environment and that this approach opens an avenue for investigating perceptual deficits and its relation to motor impairments in clinical populations.
An aminoacylation independent activity of PheRS/FARS promotes growth and proliferation

Aminoacyl-tRNA synthetases (aaRSs) not only load the appropriate amino acid onto their cognate tRNA, but many of them perform additional functions that are not necessarily related to their canonical activities. Phenylalanyl-tRNA synthetase (PheRS/FARS) levels are elevated in various cancer cells compared to their normal cell counterparts. However, whether and how these levels might contribute to tumor formation was not clear. Here, we show that PheRS is required for cell growth and proliferation. Interestingly, elevated expression of the α-PheRS subunit alone stimulates cell growth and proliferation. In the wing discs system, this leads to a strong increase of mitotic cells. Clonal analysis of twin spots in dividing follicle cells revealed that elevated expression of the α-PheRS subunit causes cells to grow and proliferate about 25% faster than their normal twin cells. Importantly, this stimulation of growth and proliferation neither required the β-PheRS subunit nor the aminoacylation activity, and it did not visibly stimulate translation. These results, therefore, revealed a non-canonical function of an ancient housekeeping enzyme, providing novel insight into its roles in health and diseases.