Miracle-dz/UniFAR-FTUs huggingface dataset:
Synaptic integration by co-localized G protein-coupled receptors in presynaptic terminals

Presynaptic terminals have been little studied as sites of synaptic integration because of inaccessibility. Gi/o-mediated presynaptic inhibition is ubiquitous and either reduces release probability (Pr) by inhibiting Ca2+ entry or inhibits directly at SNARE complexes. At CA1-subicular presynapses, 5-HT1B and GABAB receptors colocalize. GABABRs inhibit Ca2+ entry, whereas 5-HT1BRs Ca2+-dependently target SNARE complexes. We demonstrate that GABABRs, alter Pr, but 5-HT1BRs reduce cleft glutamate concentrations allowing strong inhibition of AMPA-but not NMDA-receptor responses. Simulations of glutamate release and receptor binding demonstrates that experimental effects on release and low affinity antagonism are well-fit by reduced release rates. Train-dependent presynaptic Ca2+ accumulation forces frequency-dependent recovery of neurotransmission during 5-HT1BR activation, consistent with competition between Ca2+-synaptotagmin and Gβγ at SNARE complexes. Thus, stimulus trains in 5-HT unveil dynamic synaptic modulation and a sophisticated hippocampal output filter, that itself is modulated by colocalized GABABRs which alter presynaptic Ca2+ allowing complex presynaptic integration.
Epithelial Infection With Candida albicans Elicits a Multi-System Response in Planarians

Candida albicans is one of the most common fungal pathogens of humans. Prior work introduced the planarian Schmidtea mediterranea as a new model system to study the host response to fungal infection at the organismal level. In the current study, we analyzed host-pathogen changes that occurred in situ during early infection with C. albicans. We found that the transcription factor Bcr1 and its downstream adhesin Als3 are required for C. albicans to adhere to and colonize the planarian epithelial surface, and that adherence of C. albicans triggers a multi-system host response that is mediated by the Dectin signaling pathway. This infection response is characterized by two peaks of stem cell divisions and transcriptional changes in differentiated tissues including the nervous and the excretory systems. This response bears some resemblance to a wound-like response to physical injury; however, it takes place without visible tissue damage and it engages a distinct set of progenitor cells. Overall, we identified two C. albicans proteins that mediate epithelial infection of planarians and a comprehensive host response facilitated by diverse tissues to effectively clear the infection.
Pangenome-based genome inference

Typical analysis workflows map reads to a reference genome in order to detect genetic variants. Generating such alignments introduces references biases, in particular against insertion alleles absent in the reference and comes with substantial computational burden. In contrast, recent k-mer-based genotyping methods are fast, but struggle in repetitive or duplicated regions of the genome. We propose a novel algorithm, called PanGenie, that leverages a pangenome reference built from haplotype-resolved genome assemblies in conjunction with k-mer count information from raw, short-read sequencing data to genotype a wide spectrum of genetic variation. The given haplotypes enable our method to take advantage of linkage information to aid genotyping in regions poorly covered by unique k-mers and provides access to regions otherwise inaccessible by short reads. Compared to classic mapping-based approaches, our approach is more than 4× faster at 30× coverage and at the same time, reached significantly better genotype concordances for almost all variant types and coverages tested. Improvements are especially pronounced for large insertions (> 50bp), where we are able to genotype > 99.9% of all tested variants with over 90% accuracy at 30× short-read coverage, where the best competing tools either typed less than 60% of variants or reached accuracies below 70%. PanGenie now enables the inclusion of this commonly neglected variant type in downstream analyses.
Brief history of spaser from conception to the future

Abstract. A history and a glimpse into the future of spaser (acronym for “surface plasmon amplification by stimulated emission of radiation”) is provided. The spaser (also called a plasmonic nanolaser) is an active nanosystem including a gain medium and a nanoplasmonic metal core. It generates coherent intense nanolocalized fields. Theoretically predicted in 2003 by Bergman and Stockman, the spaser grew into a large fundamental research and application field with thousands of publications. We review a few of them to illustrate the most important and general fundamental properties of the spaser. We also review some selected applications of spasers, in particular, to ultrasensing and biomedical problems, concentrating on cancer-cell theranostics (therapeutics and diagnostics). In conclusion, we attempt to glimpse into the future by predicting that the next big development of the spasers will be topological nano-optics, and its “killer” application will be ultrafast, high-density on-chip communications for future information processing.
The distinct roles of calcium in rapid control of neuronal glycolysis and the tricarboxylic acid cycle

When neurons engage in intense periods of activity, the consequent increase in energy demand can be counteracted by the coordinated activation of glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. However, the trigger for glycolytic activation is unknown and the role for Ca2+ in the mitochondrial responses has been debated. Using genetically-encoded fluorescent biosensors and NAD(P)H autofluorescence imaging in acute hippocampal slices, here we find that Ca2+ uptake into the mitochondria is responsible for the buildup of mitochondrial NADH, probably through Ca2+ activation of dehydrogenases in the TCA cycle. In the cytosol, we do not observe a role for the Ca2+/calmodulin signaling pathway, or AMPK, in mediating the rise in glycolytic NADH in response to acute stimulation. Calcium, nevertheless, is a major contributor to glycolysis, although not strictly necessary. Aerobic glycolysis in neurons is triggered mainly by the energy demand resulting from either Na+ or Ca2+ extrusion. Impact Statement When neurons are stimulated, calcium influx instructs mitochondria to increase energy metabolism, but it is increased energy demand in cytosol rather than Ca2+ signaling that leads to increased neuronal glycolysis.
Comparison of changes in electrical activity, in isolated and in vivo hearts, induced by voluntary exercise in female rats

Regular mild exercise is recommended to the general population as beneficial to health. Regular exercise typically leads to structural and electrical remodelling of the heart but in human studies it is difficult to relate the extrinsic and intrinsic influences on intact hearts to changes seen at the single cell level. In this study we wished to test whether changes in electrical activity in intact hearts, in response to voluntary wheel running exercise training, were consistent with our previous observations in single cardiac myocytes and whether these changes resulted in altered susceptibility to arrhythmic stimuli. Female rats performed 5 weeks of voluntary wheel running. Implanted telemetry transmitters were used to measure electrocardiograms (ECGs) and determine heart rate variability (HRV) in conscious, unrestrained, trained (TRN) and sedentary (SED) animals. In isolated hearts, left ventricular epicardial monophasic action potentials (MAPs) were recorded and the responses to potentially arrhythmic interventions were assessed. Exercise training caused cardiac hypertrophy, as indexed by a significantly greater heart weight to body weight ratio. Consistent with previous measurements of action potential duration in single myocytes, MAPs were significantly longer at 50%, 75% and 90% repolarization. Arrhythmic susceptibility was not different between SED and TRN hearts. Trained animals displayed significantly altered HRV by week 5, in a manner consistent with reduced sympathetic tone, however resting ECG parameters, including those most associated with repolarisation duration, were unaltered. We conclude that intrinsic changes to cellular cardiac electrophysiology, induced by mild voluntary exercise, are not attenuated by the electronic loading that occurs in intact hearts. However, in vivo, extrinsic neuro-hormonal control of the heart may minimize the effects of intrinsic alterations in electrical activity.
Cell autonomous TGF-beta signaling is essential for cell recruitment into degenerating tendons

Understanding the role of cell recruitment in tendon disorders is critical for improvements in regenerative therapy. We recently reported that targeted disruption of TGFβ type II receptor in the tendon cell lineage (Tgfbr2ScxCre) resulted in tenocyte dedifferentiation and tendon degradation in post-natal stages. Here we extend the analysis and identify direct recruitment of stem/progenitor cells into the degenerative mutant tendons. Cre-lineage tracing indicates that these cells are not derived from tendon ensheathing tissues or from a Scleraxis-lineage, and they turned on tendon markers only upon entering the mutant tendons. Through immunohistochemistry and inducible gene deletion, we further find that the recruited cells originated from a Sox9-expressing lineage and their recruitment was dependent on cell-autonomous TGFβ signaling. These results thus differ from previous reports of cell recruitment into injured tendons, and suggest a critical role for TGFβ signaling and cell recruitment in the etiology and treatment of tendon degeneration.
Leveraging Hardy–Weinberg disequilibrium for association testing in case-control studies

In a case-control association study, deviation from Hardy-Weinberg equilibrium (HWE) or Hardy-Weinberg dis-equilibrium (HWD) in the control group is usually considered as evidence for potential genotyping error, and the corresponding SNP is then removed from the study. On the other hand, assuming HWE holds in the study population, a truly associated SNP is expected to be out of HWE in the case group. Efforts have been made in combining association tests with tests of HWE in the cases to increase the power of detecting disease susceptibility loci (Song and Elston (2006), Wang and Shete (2010)). However, these existing methods are ad-hoc and sensitive to model assumptions. Utilizing the recent robust allele-based (RA) regression model for conducting allelic association tests (Zhang and Sun (2020)), here we propose a joint RA test that naturally integrates association evidence from the traditional association test and a test that evaluates the difference in HWD between the case and control groups. The proposed test is robust to genotyping error, as well as to potential HWD in the population attributed to factors that are unrelated to phenotype-genotype association. We provide the asymptotic distribution of the proposed test statistic so that it is easy to implement, and we demonstrate the accuracy and efficiency of the test through extensive simulation studies and an application.
Inhibiting corticospinal excitability by entraining ongoing mu-alpha rhythm in motor cortex

Sensorimotor mu-alpha rhythm reflects the state of cortical excitability. Repetitive transcranial magnetic stimulation (rTMS) can modulate neural synchrony by inducing periodic electric fields (E-fields) in the cortical networks. We hypothesized that the increased synchronization of mu-alpha rhythm would inhibit the corticospinal excitability reflected by decreased motor evoked potentials (MEP). In seventeen healthy participants, we applied rhythmic, arrhythmic, and sham rTMS over the left M1. The stimulation intensity was individually adapted to 35 mV/mm using prospective E-field estimation. This intensity corresponded to ca. 40% of the resting motor threshold. We found that rhythmic rTMS increased the synchronization of mu-alpha rhythm, increased mu-alpha/beta power, and reduced MEPs. On the other hand, arrhythmic rTMS did not change the ongoing mu-alpha synchronization or MEPs, though it increased the alpha/beta power. We concluded that low intensity, rhythmic rTMS can synchronize mu-alpha rhythm and modulate the corticospinal excitability in M1. Highlights We studied the effect of rhythmic rTMS induced E-field at 35 mV/mm in the M1 Prospective electric field modeling guided the individualized rTMS intensities Rhyhtmic rTMS entrained mu-alpha rhythm and modulated mu-alpha/beta power Arrhythmic rTMS did not synchronize ongoing activity though increased mu-alpha/beta power. Rhythmic but not arrhythmic or sham rTMS inhibited the cortical excitability in M1
Aversive Conditioning of Spatial Position Sharpens Neural Population-Level Tuning in Visual Cortex and Selectively Alters Alpha-Band Activity

Processing capabilities for many low-level visual features are experientially malleable, aiding sighted organisms in adapting to dynamic environments. Explicit instructions to attend a specific visual field location influence retinotopic visuocortical activity, amplifying responses to stimuli appearing at cued spatial positions. It remains undetermined both how such prioritization affects surrounding nonprioritized locations, and if a given retinotopic spatial position can attain enhanced cortical representation through experience rather than instruction. The current report examined visuocortical response changes as human observers (N = 51, 19 male) learned, through differential classical conditioning, to associate specific screen locations with aversive outcomes. Using dense-array EEG and pupillometry, we tested the preregistered hypotheses of either sharpening or generalization around an aversively associated location following a single conditioning session. Competing hypotheses tested whether mean response changes would take the form of a Gaussian (generalization) or difference-of-Gaussian (sharpening) distribution over spatial positions, peaking at the viewing location paired with a noxious noise. Occipital 15 Hz steady-state visual evoked potential responses were selectively heightened when viewing aversively paired locations and displayed a nonlinear, difference-of-Gaussian profile across neighboring locations, consistent with suppressive surround modulation of nonprioritized positions. Measures of alpha-band (8–12 Hz) activity were differentially altered in anterior versus posterior locations, while pupil diameter exhibited selectively heightened responses to noise-paired locations but did not evince differences across the nonpaired locations. These results indicate that visuocortical spatial representations are sharpened in response to location-specific aversive conditioning, while top-down influences indexed by alpha-power reduction exhibit posterior generalization and anterior sharpening. SIGNIFICANCE STATEMENT It is increasingly recognized that early visual cortex is not a static processor of physical features, but is instead constantly shaped by perceptual experience. It remains unclear, however, to what extent the cortical representation of many fundamental features, including visual field location, is malleable by experience. Using EEG and an aversive classical conditioning paradigm, we observed sharpening of visuocortical responses to stimuli appearing at aversively associated locations along with location-selective facilitation of response systems indexed by pupil diameter and EEG alpha power. These findings highlight the experience-dependent flexibility of retinotopic spatial representations in visual cortex, opening avenues toward novel treatment targets in disorders of attention and spatial cognition.
Ribosome quality control activity potentiates vaccinia virus protein synthesis during infection

Ribosomes are highly abundant cellular machines that perform the essential task of translating the genetic code into proteins. Cellular translation activity is finely tuned and proteostasis insults, such as those incurred upon viral infection, activate stress signaling pathways that result in translation reprogramming. Viral infection selectively shuts down host mRNA while redistributing ribosomes for selective translation of viral mRNAs. The intricacies of this selective ribosome shuffle from host to viral mRNAs are poorly understood. Here, we uncover a role for the ribosome associated quality control (RQC) factor ZNF598, a sensor for collided ribosomes, as a critical factor for vaccinia virus mRNA translation. Collided ribosomes are sensed by ZNF598, which ubiquitylates 40S subunit proteins uS10 and eS10 and thereby initiates RQC-dependent nascent chain degradation and ribosome recycling. We show that vaccinia infection in human cells enhances uS10 ubiquitylation indicating an increased burden on RQC pathways during viral propagation. Consistent with an increased RQC demand, we demonstrate that vaccinia virus replication is impaired in cells which either lack ZNF598 or contain a ubiquitylation deficient version of uS10. Using SILAC-based proteomics and concurrent RNAseq analysis, we determine that host translation of vaccinia virus mRNAs is compromised in cells that lack RQC activity as compared to control cells whereas there was little evidence of differences in host or viral transcription. Additionally, vaccinia virus infection resulted in a loss of cellular RQC activity, suggesting that ribosomes engaged in viral protein production recruit ZNF598 away from its function in host translation. Thus, co-option of ZNF598 by vaccinia virus plays a critical role in translational reprogramming that is needed for optimal viral propagation.
Data-driven streamflow modelling in ungauged basins: regionalizing random forest (RF) models

Streamflow predictions in ungauged basins (PUB) has been geared towards data-driven methods, including the use of machine learning methods such as random forest (RF). Such methods are applied in PUB regionalization or the transfer of a streamflow model from gauged to ungauged (sub) basins or watersheds after grouping watersheds on similarity rules. Regionalized streamflow models are needed for tropical-mountainous regions like Luzon, Philippines - where gauged data is limited - but demands on streamflow modelling for water resources accounting and management are high. In 21 watersheds in Luzon, we “regionalize” RF streamflow models after grouping watersheds based on: a principal components analysis (PCA-clustered), by major river basins (basin-clustered), whole study area scale (one-clustered). Another method without watershed grouping (watershed-level) was also included and inter-compared. Among the four methods, goodness-of-fit evaluations revealed that PCA-clustered method was higher by at most 0.35 coefficient of determination R2 and 0.31 nash-sutcliffe efficiency NSE, and the least bias in 8 of 12 monthly flows. These are attributed to the added-value of homogeneous watershed grouping, reflected by higher importance (to RF models), of static covariates from open and high-resolution data. Normalized errors from monthly streamflow showed a clear bias (least with the PCA-clustered metohd), linked to season and water management practices in the study area. Ungauged watersheds in the Philippines can effectively use streamflow models from gauged watersheds if they belong to the same cluster. Key Points Ungauged sub-basins (watersheds) can effectively use RF streamflow models from gauged watersheds if both belong to the same cluster. Biophysical data from high-resolution open data are valuable: as basis for watershed clustering and as streamflow predictors to RF models. The predicted streamflow from the RF models reflects seasonal deviations in streamflow caused by natural and man-made water regulation
Chondrocytes in the resting zone of the growth plate are maintained in a Wnt-inhibitory environment

Chondrocytes in the resting zone of the postnatal growth plate are characterized by slow cell cycle progression, and encompass a population of parathyroid hormone-related protein (PTHrP)-expressing skeletal stem cells that contribute to the formation of columnar chondrocytes. However, how these chondrocytes are maintained in the resting zone remains undefined. We undertook a genetic pulse-chase approach to isolate slow cycling, label-retaining chondrocytes (LRCs) from the growth plate using a chondrocyte-specific doxycycline-controllable Tet-Off system regulating expression of histone 2B-linked GFP. Comparative RNA-seq analysis identified significant enrichment of inhibitors and activators for Wnt/β-catenin signaling in LRCs and non-LRCs, respectively. Activation of Wnt/β-catenin signaling in PTHrP+ resting chondrocytes using Pthrp-creER and Apc-floxed allele impaired their ability to form columnar chondrocytes. Therefore, slow-cycling chondrocytes are maintained in a canonical Wnt-inhibitory environment within the resting zone, unraveling a novel mechanism regulating maintenance and differentiation of PTHrP+ skeletal stem cells of the postnatal growth plate.
The Network Analysis Profiler (NAP v2.0): A web tool for visual topological comparison between multiple networks

In this article we present the Network Analysis Profiler (NAP v2.0), a web tool to directly compare the topological features of multiple networks simultaneously. NAP is written in R and Shiny and currently offers both 2D and 3D network visualization as well as simultaneous visual comparisons of node- and edge-based topological features both as bar charts or as a scatterplot matrix. NAP is fully interactive and users can easily export and visualize the intersection between any pair of networks using Venn diagrams or a 2D and a 3D multi-layer graph-based visualization. NAP supports weighted, unweighted, directed, undirected and bipartite graphs and is available at: http://bib.fleming. gr:3838/NAP/. Its code can be found at: https://github.com/PavlopoulosLab/NAP
Location Data Analytics in the Business Value Chain: A Systematic Literature Review

Context information has become a significant asset to optimize the value obtained from information systems. Location is an important type of context information that refers to the place in which an event occurs. In business environments, the implementation of location-based analytics systems to aid decision making processes is of paramount importance for business development. However, after an exhaustive literature review, we found that researchers and practitioners still lack a comprehensive characterization of location-based data analytics systems that have been effectively applied to business processes. This paper presents the results of a systematic literature review (SLR), in which we characterized a total of 168 location-based and business oriented analytics solutions that were published between 2014 and 2019. To conduct this SLR we defined three characterization dimensions: business aspects, through which we identified value chain business processes or activities that may be benefited with the proposed solution; data source, which allowed us to report on the data used in each of the studies; and data analytics, through which we report on the analytics techniques and validation strategies implemented by the studied approaches. The contribution of our SLR is twofold. First, it provides business and data analytics practitioners with a comprehensive catalog of location-based data analytics approaches that could be applied to improve value generation, at different levels, along their businesses’ value chains. And second, it provides researchers with a complete landscape of recent advancements and open challenges in the field.