Miracle-dz/UniFAR-FTUs huggingface dataset:
Counterintuitive Binding of Phosphorylated DEP Domain from Dishevelled Protein to Negatively Charged Membranes

To accomplish its role of signaling hub in all Wnt signaling pathways, Dishevelled (DVL) protein needs to dynamically relocalize to the inner leaflet of the cellular plasma membrane (PM). Combined experimental and computational evidence showed that the binding of DVL to the PM is mainly driven by the electrostatic attraction between a stretch of positively charged amino acids located on the C-terminal DEP domain of DVL and anionic phospholipid species, with a striking preference for phosphatidic acid (PA). Here, by means of computational simulations and QCM-D experiments, we demonstrate that four recently identified phosphorylation sites on DEP domain, alter the electrostatic potential of the membrane binding interface, but do not prevent the recruitment to anionic membranes. On the contrary, the phosphorylated residues are involved in hydrogen bond and ion-mediated interactions with the lipid headgroup of PA. Our results suggest that the effect of phosphorylation on protein-membrane association could be counterintuitive and sensitive to changes in the local environment including specific lipids, salts, and pH. SIGNIFICANCE Phosphorylation regulates the cellular activity and localization of many peripheral proteins by, among others, decreasing the affinity for negatively charged membranes. Here, we report how phosphorylation affects the membrane interaction of DEP domain from Dishevelled protein, the intracellular signaling hub in Wnt pathways. We found that despite the negative charge induced by phosphorylation, DEP domain was steadily adsorbed to the surface of negatively charged PA-rich membranes, due to a dense network of cation-mediated interactions and hydrogen bonds.
Considering dynamic nature of the brain: the clinical importance of connectivity variability in machine learning classification and prediction

The brain connectivity of resting-state fMRI (rs-fMRI) represents an intrinsic state of brain architecture, and it has been used as a useful neural marker for detecting psychiatric conditions as well as for predicting psychosocial characteristics. However, most studies using brain connectivity have focused more on the strength of functional connectivity over time (static-FC) but less attention to temporal characteristics of connectivity changes (FC-variability). The primary goal of the current study was to investigate the effectiveness of using the FC-variability in classifying an individual’s pathological characteristics from others and predicting psychosocial characteristics. In addition, the current study aimed to prove that benefits of the FC-variability are reliable across various analysis procedures. To this end, three open public large resting-state fMRI datasets including individuals with Autism Spectrum Disorder (ABIDE; N = 1249), Schizophrenia disorder (COBRE; N = 145), and typical development (NKI; N = 672) were utilized for the machine learning (ML) classification and prediction based on their static-FC and the FC-variability metrics. To confirm the robustness of FC-variability utility, we benchmarked the ML classification and prediction with various brain parcellations and sliding window parameters. As a result, we found that the ML performances were significantly improved when the ML included FC-variability features in classifying pathological populations from controls (e.g., individuals with autism spectrum disorder vs. typical development) and predicting psychiatric severity (e.g., score of autism diagnostic observation schedule), regardless of parcellation selection and sliding window size. Additionally, the ML performance deterioration was significantly prevented with FC-variability features when excessive features were inputted into the ML models, yielding more reliable results. In conclusion, the current finding proved the usefulness of the FC-variability and its reliability.
Dynamic fate map of hindbrain rhombomeres in zebrafish

Understanding of the morphogenetic processes that underlie the patterning of the vertebrate hindbrain requires establishment of rhombomere (r) cell lineages. Using long term in vivo two-photon imaging of zebrafish transgenic lines and automated image processing tools, we provide a method to reconstruct the r2-r6 lineage trees from the onset of gastrulation through early neurulation. We provide a dynamic fate map of hindbrain patterning at single-cell resolution. We show that rhombomere progenitor domains are aligned along the anteroposterior (AP) and dorsoventral (DV) axes as early as the shield stage. Rhombomere progenitor domains show a segmental organization, parallel to the blastoderm margin that predicts the future AP order of hindbrain. The DV organization of rhombomeres is set by the segregation of the progenitors along the DV axis of the embryo. Progenitors located at the dorsal/medial part of the blastoderm form the ventral domain of the rhombomeres while the lateral progenitors constitute the dorsal part. Our study sheds light on the clonal origin of individual rhombomeres, spatial and temporal patterns of cell division and migration of rhombomere progenitors throughout the early steps of hindbrain morphogenesis.
Single-cell transcriptome dynamics of the autotaxin-lysophosphatidic acid axis during muscle regeneration reveal proliferative effects in mesenchymal fibro-adipogenic progenitors

Lysophosphatidic acid (LPA) is a growth factor-like bioactive phospholipid recognising LPA receptors (LPARs) and mediating signalling pathways that regulate embryonic development, wound healing, carcinogenesis, and fibrosis, via effects on cell migration, proliferation and differentiation. Extracellular LPA is generated from lysophospholipids by the secreted hydrolase - ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2; also, AUTOTAXIN / ATX) and metabolised by different membrane-bound phospholipid phosphatases (PLPPs). Here, we use public bulk and singlecell RNA sequencing datasets to explore the gene expression of Lpar1-6, Enpp2, and Plpp genes under skeletal muscle homeostasis and regeneration conditions. We show that the skeletal muscle system dynamically expresses the Enpp2-Lpar-Plpp gene axis, with Lpar1 being the highest expressed member among LPARs. Lpar1 was expressed by mesenchymal fibro-adipogenic progenitors (FAPs) and tenocytes, whereas FAPs mainly expressed Enpp2. Clustering of FAPs identified populations representing distinct cell states with robust Lpar1 and Enpp2 transcriptome signatures in homeostatic cells expressing higher levels of markers Dpp4 and Hsd11b1. However, tissue injury induced transient repression of Lpar genes and Enpp2. The role of LPA in modulating the fate and differentiation of tissue-resident FAPs has not yet been explored. Ex vivo, LPAR1/3 and ENPP2 inhibition significantly decreased the cell-cycle activity of FAPs and impaired fibro-adipogenic differentiation, implicating LPA signalling in the modulation of the proliferative and differentiative fate of FAPs. Together, our results demonstrate the importance of the ENPP2-LPAR-PLPP axis in different muscle cell types and FAP lineage populations in homeostasis and injury, paving the way for further research on the role of this signalling pathway in skeletal muscle homeostasis and regeneration, and that of other organs and tissues, in vivo. Summary Our reanalysis of single-cell transcriptomics revealed the involvement and temporally dynamic expression of the ENPP2-LPAR-PLPP axis in response to skeletal muscle regeneration.
Investigation of a Severe Downburst Storm near Phoenix, Arizona, as Seen by a Mobile Doppler Radar and the KIWA WSR-88D

Abstract A Shared Mobile Atmospheric Research and Teaching Radar (SMART-R) was deployed near Phoenix, Arizona, during the summer of 2004. The goal was to capture a severe microburst at close range to understand the low-altitude wind structure and evolution. During the evening of 27 July, a severe storm formed along the Estrella Mountains south of Phoenix and moved south of the SMART-R as well as the National Weather Service’s (NWS) Weather Surveillance Radar-1988 Doppler (WSR-88D) in Phoenix (KIWA). Several microburst–downburst pulses were observed by radar and a surface wind gust of 67 mi h−1 was reported. The radar data illustrate the finescale structure of the microburst pulses, with the SMART-R’s higher-resolution data showing Doppler velocities 3–4 m s−1 greater than the KIWA radar. SMART-R wind shear values were 2–3 times greater with the finer resolution of the SMART-R revealing smaller features in the surface outflow wind structure. Asymmetric outflow may have been a factor as well in the differen.
The Gas-Drag Effect on the Orbital Instability of a Protoplanet System

We have investigated numerically the orbital instability of a protoplanet system while taking account of the gasdrag force due to the solar nebula. In the present work, we considered an equally spaced five-protoplanet (with the same mass of 1 ×10 −7 M� ) system, in which their initial orbits are coplanar and circular, and assumed that the gas-drag force is proportional to the square of the relative velocity between the gas and a protoplanet. We first reexamined and confirmed that, under a gas-free condition, log 10 Tinst can be approximately written as a linear function of the initial orbital separation distance, ∆˜ a0, where Tinst is the time of the orbital instability (i.e., the time of the first orbital crossing between any two protoplanets). Next, we investigated the instability time under the gas-drag effect, T gas inst , and found that T gas inst suddenly becomes large compared with Tinst, when ∆˜ a0 is larger than a certain critical separation distance, (∆˜ a0)crit. Furthermore, we showed that (∆˜ a0)crit can be described semi-analytically as a function of the gaseous density. From a function extrapolated with a density in the minimum mass nebula model, we estimated (∆˜ a0)crit in the nebula as being about 10 Hill radius at 1 AU.
Neural substrates of parallel devaluation-sensitive and devaluation-insensitive Pavlovian learning in humans

Pavlovian learning depends on multiple and parallel associations leading to distinct classes of conditioned responses that vary in their flexibility following changes in the value of an associated outcome. Here, we aimed to differentiate brain areas involved in learning and encoding associations that are sensitive to changes in the value of an outcome from those that are not sensitive to such changes. To address this question, we combined a Pavlovian learning task with outcome devaluation, eye–tracking and functional magnetic resonance imaging. We used computational modeling to identify brain regions involved in learning stimulus-reward associations and stimulus–stimulus associations, by testing for brain areas correlating with reward–prediction errors and state-prediction errors, respectively. We found that, contrary to theoretical predictions about reward prediction errors being exclusively model–free, voxels correlating with reward prediction errors in the ventral striatum and subgenual anterior cingulate cortex were sensitive to devaluation. On the other hand, brain areas correlating with state prediction errors were found to be devaluation insensitive. In a supplementary analysis, we distinguished brain regions encoding predictions about outcome taste identity from those involved in encoding predictions about its expected spatial location. A subset of regions involved in taste identity predictions were devaluation sensitive while those involved in encoding predictions about spatial location were devaluation insensitive. These findings provide insights into the role of multiple associative mechanisms in the brain in mediating Pavlovian conditioned behavior – illustrating how distinct neural pathways can in parallel produce both devaluation sensitive and devaluation insensitive behaviors.
Molten globule driven and self-downmodulated phase separation of a viral factory scaffold

Viral factories of liquid-like nature host transcription and replication in most viruses. The syncytial respiratory virus factories include gene function proteins, brought together by the phosphoprotein (P) RNA polymerase cofactor, present across non-segmented negative stranded RNA viruses. Homotypic liquid-liquid phase separation of RSV-P is governed by an α-helical molten globule domain, and strongly self-downmodulated by adjacent sequences. Condensation of P with the nucleoprotein N is stoichiometrically tuned, defining aggregate-droplet and droplet-dissolution boundaries. Time course analysis show small N-P nuclei gradually coalescing into large granules in transfected cells. This behavior is recapitulated in infection, with small puncta evolving to large viral factories, strongly suggesting that P-N nucleation-condensation sequentially drives viral factories. Thus, the tendency of P to undergo phase separation is moderate and latent in the full-length protein but unleashed in the presence of N or when neighboring disordered sequences are deleted. This, together with its capacity to rescue nucleoprotein-RNA aggregates suggests a role as a “solvent-protein” and possible fluidity tuner of viral factories.
Age‐specific impacts of vegetation functional traits on gastrointestinal nematode parasite burdens in a large herbivore

Gastro-intestinal nematode (GIN) parasites play an important role in the ecological dynamics of many animal populations. Recent studies suggest fine-scale spatial variation in GIN infection dynamics are important in wildlife systems, but the environmental drivers underlying this variation remain poorly understood. We used data from over two decades of GIN parasite egg counts, host space use, and spatial vegetation data from a long-term study of Soay sheep on St Kilda to test how spatial autocorrelation and vegetation in an individual’s home range predict parasite burden across three age groups. We developed a novel approach to quantify the plant functional traits present in a home range to describe the quality of vegetation present. Effects of space and vegetation varied between age classes. In immature lambs, strongyle parasite faecal egg counts (FEC) were spatially structured, being highest in the north and south of our study area. Independent of host body weight and spatial autocorrelation, plant functional traits predicted parasite egg counts. Higher egg counts were associated with more digestible and preferred plant functional traits, suggesting the association could be driven by host density and habitat preference. In contrast, we found no evidence that parasite FEC were related to plant functional traits in the host home range in yearlings or adult sheep. Adult FEC were spatially structured, with highest burdens in the north-east of our study area, while yearling FEC showed no evidence of spatial structuring. Our findings support the importance of fine-scale environmental variation for wildlife disease ecology and provides new evidence that such effects may vary across demographic groups within a population. Parasite burdens in immature individuals appear more readily influenced by fine-scale spatial variation in the environment, highlighting the importance of such heterogeneity for our understanding of wildlife epidemiology and health.
Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation

Midbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinson’s disease (PD). Many transcription factors (TFs) controlling human mDAN differentiation during development have been described, but much of the regulatory landscape remains undefined. Using a tyrosine hydroxylase (TH) iPSC reporter line, we have generated time series transcriptomic and epigenomic profiles of purified mDANs during differentiation. Integrative analysis predicted novel central regulators of mDAN differentiation and super-enhancers were used to prioritize key TFs. We find LBX1, NHLH1 and NR2F1/2 to be necessary for mDAN differentiation and show that overexpression of either LBX1 or NHLH1 can also improve mDAN specification. NHLH1 is necessary for the induction of neuronal miR-124, while LBX1 regulates cholesterol biosynthesis, possibly through mTOR signaling. Consistently, rapamycin treatment led to an inhibition of mDAN differentiation. Thus, our work reveals novel regulators of human mDAN differentiation.
Different time encoding strategies within the medial premotor areas of the primate

The measurement of time in the subsecond scale is critical for many sophisticated behaviors, yet its neural underpinnings are largely unknown. Recent neurophysiological experiments from our laboratory have shown that the neural activity in the medial premotor areas (MPC) of macaques can represent different aspects of temporal processing. During interval categorization, we found that preSMA encodes a subjective category limit by reaching a peak of activity at a time that divides the set of test intervals into short and long. We also observed neural signals associated with the category selected by the subjects and the reward outcomes of the perceptual decision. On the other hand, we have studied the behavioral and neurophysiological basis of rhythmic timing. First, we have shown in different tapping tasks that macaques are able to produce predictively and accurately intervals that are cued by auditory or visual metronomes or when intervals are produced internally without sensory guidance. In addition, we found that the rhythmic timing mechanism in MPC is governed by different layers of neural clocks. Next, the instantaneous activity of single cells shows ramping activity that encode the elapsed or remaining time for a tapping movement. In addition, we found MPC neurons that build neural sequences, forming dynamic patterns of activation that flexibly cover all the produced interval depending on the tapping tempo. This rhythmic neural clock resets on every interval providing an internal representation of pulse. Furthermore, the MPC cells show mixed selectivity, encoding not only elapsed time, but also the tempo of the tapping and the serial order element in the rhythmic sequence. Hence, MPC can map different task parameters, including the passage of time, using different cell populations. Finally, the projection of the time varying activity of MPC hundreds of cells into a low dimensional state space showed circular neural trajectories whose geometry represent the internal pulse and the tapping tempo. Overall, these findings support the notion that MPC is part of the core timing mechanism for both single interval and rhythmic timing, using neural clocks with different encoding principles, probably to flexibly encode and mix the timing representation with other task parameters.
Bicrystal structure of tilted perpendicular media for ultra-high-density recording

A modified tilted perpendicular medium has been proposed. With crystalline easy axes oriented randomly at ±45° relative to the perpendicular direction in the cross-track plane, the in-plane magnetic charges in the uniformly tilted perpendicular media can be effectively eliminated. Recording properties of the tilted perpendicular media are studied via micromagnetic simulation. In addition to the advantage of less saturation field, titled perpendicular media also show improved recording performance as compared to the conventional perpendicular media.
On the control of spatial and temporal oceanic scales by existing and future observing systems: An observing system simulation experiment approach

Ocean monitoring and forecasting systems combine information from ocean observations and numerical models through advanced data assimilation techniques. They are essential to monitor and report on past, present and future oceanic conditions. However, given the continuous development of oceanic models and data assimilation techniques in addition to the increased diversity of assimilated platforms, it becomes more and more difficult to establish how information from observations is used, and to determine the utility and relevance of a change of the global ocean observing system on ocean analyses. Here, a series of observing system simulation experiments (OSSE), which consist in simulating synthetic observations from a realistic simulation to be subsequently assimilated in an experimental analysis system, was performed. An original multiscale approach is then used to investigate (i) the impact of various observing system components by distinguishing between satellites and in situ (Argo floats and tropical moorings), and (ii) the impact of recommended changes in observing systems, in particular the impact of Argo floats doubling and enhancements of tropical moorings, on the fidelity of ocean analyses. This multiscale approach is key to better understand how observing system components, with their distinct sampling characteristics, help to constrain physical processes. The study demonstrates the ability of the analysis system to represent 40-80% of the temperature variance at mesoscale (20-30% for salinity), and more than 80% for larger scales. Satellite information, mostly through altimetric data, strongly constrains mesoscale variability, while the impact of in situ temperature and salinity profiles are essential to constrain large scale variability. It is also shown that future enhancements of Argo and tropical mooring arrays observations will likely be beneficial to ocean analyses at both intermediate and large scales, with a higher impact for salinity-related quantities. This work provides a better understanding on the respective role of major satellite and in situ observing system components in the integrated ocean observing system.
Short-term effects of ambient air pollution on emergency department visits for urolithiasis: A time-series study in Wuhan, China

Background Previous studies have explored the correlation between short-term exposure to air pollution and urinary system diseases, but lack of evidence on the correlation between air pollution and urolithiasis. Methods Daily data of emergency department visits (EDVs), concentrations of six air pollutants (SO2, NO2, PM2.5, PM10, CO, and O3) and meteorological variables were collected in Wuhan, China, from 2016 to 2018. And a time-series study was conducted to investigate short-term effects of air pollutants on urolithiasis EDVs. In addition, stratified analyses by season, age and gender were also conducted. Results A total of 7,483 urolithiasis EDVs were included during the study period. A 10-μg/m3 increase of SO2, NO2, PM2.5, CO, PM10, and O3 corresponded to 15.02% (95% confidence interval [CI]: 1.69%, 30.11%), 1.96% (95% CI: 0.19%, 3.76%), 1.09% (95% CI:−0.24%, 2.43%), 0.14% (95% CI: 0.02%, 0.26%), 0.72% (95% CI: 0.02%, 1.43%), and 1.17% (95% CI: 0.40%, 1.94%) increases in daily urolithiasis EDVs. Significant positive correlations were observed between SO2, NO2, CO, and O3 and urolithiasis EDVs. The correlations were mainly among females (especially PM2.5 and CO) and younger people (especially SO2, NO2, and PM10) but the effect of CO was more obvious in elders. Furthermore, the effects of SO2 and CO were stronger in warm seasons, while the effects of NO2 were stronger in cool seasons. Conclusion Our time-series study indicates that short-term exposure to air pollution (especially SO2, NO2, CO, and O3) was positively correlated with EDVs for urolithiasis in Wuhan, China, and the effects varied by season, age and gender.