Miracle-dz/UniFAR-FTUs huggingface dataset:
Chameleon microRNAs in breast cancer: their elusive role as regulatory factors in cancer progression

Breast cancer is one of the most frequent cancers affecting women. Non-coding micro RNAs (miRNAs) seem to play an important role in the regulation of pathways involved in tumor occurrence and progression. Extending on the research in Haakensen et al., where significant miRNAs were selected as being associated with the progression from normal breast tissue to breast cancer, in this work we put forward 112 sets of miRNA combinations, each including at most 5 expressions with high accuracy in discriminating healthy breast tissue from breast carcinoma. Our results are based on a recently developed machine learning technique which, instead of selecting a single model (or combination of features), delivers a set of models with equivalent predictive capabilities that allow to interpret and visualize the interaction of these features. These results shed new light on the biological action of the selected miRNAs which can behave in different ways according to the miRNA network with which they interact. Indeed, these revealed connections may contribute to explain why, in some cases, different studies attribute opposite functions to the same miRNA. It is therefore possible to understand how the role of a genomic variable may change when considered in interaction with other sets of variables, as opposed to only considering its effect when it is evaluated within a unique combination of features. The approach proposed in this work provides a statistical basis for the notion of chameleon miRNAs and is inspired by the emerging field of systems biology. Author Summary The notion of a single predictive genomic (statistical) model is replaced by that of a set of models that can be considered as exchangeable due to their indistinguishable (optimal) predictive abilities; Our results indicate that the role of miRNAs cannot be interpreted independently from the combination of features with which they interact and can therefore vary considerably when considered in a network of different combinations. Some miRNAs may act as chameleons and behave in opposite manners thereby showing some kind of antagonistic duality; Some miRNAs are exchangeable inside models with equivalent predictive ability and seem to point to latent biological functions.
Effects of working memory load and CS-US intervals on delay eyeblink conditioning

Eyeblink conditioning is used in many species to study motor learning and make inferences about cerebellar function. However, the discrepancies in performance between humans and other species combined with evidence that volition and awareness can modulate learning suggest that eyeblink conditioning is not merely a passive form of learning that relies on only the cerebellum. Here we explored two ways to reduce the influence of volition and awareness on eyeblink conditioning: (1) using a short interstimulus interval, and (2) having participants do working memory tasks during the conditioning. Our results show that participants trained with short interstimulus intervals (150 ms and 250 ms) produce very few conditioned responses after 100 trials. Participants trained with a longer interstimulus interval (500 ms) who simultaneously did working memory tasks produced fewer conditioned responses than participants who watched a movie during the training. Our results suggest that having participants perform working memory tasks during eyeblink conditioning can be a viable strategy for studying cerebellar learning that is absent of influences from awareness and volition. This could enhance the comparability of the results obtained in human studies with those in animal models.
Alpha-Tubulin Acetylation in Trypanosoma cruzi: A Dynamic Instability of Microtubules Is Required for Replication and Cell Cycle Progression

Trypanosomatids have a cytoskeleton arrangement that is simpler than what is found in most eukaryotic cells. However, it is precisely organized and constituted by stable microtubules. Such microtubules compose the mitotic spindle during mitosis, the basal body, the flagellar axoneme and the subpellicular microtubules, which are connected to each other and also to the plasma membrane forming a helical arrangement along the central axis of the parasite cell body. Subpellicular, mitotic and axonemal microtubules are extensively acetylated in Trypanosoma cruzi. Acetylation on lysine (K) 40 of α-tubulin is conserved from lower eukaryotes to mammals and is associated with microtubule stability. It is also known that K40 acetylation occurs significantly on flagella, centrioles, cilia, basal body and the mitotic spindle in eukaryotes. Several tubulin posttranslational modifications, including acetylation of K40, have been catalogued in trypanosomatids, but the functional importance of these modifications for microtubule dynamics and parasite biology remains largely undefined. The primary tubulin acetyltransferase that delivers this modification was recently identified in several eukaryotes as Mec-17/ATAT, a Gcn5-related N-acetyltransferase. Here, we report that T. cruzi ATAT acetylates α-tubulin in vivo and is capable of auto-acetylation. TcATAT is located in the cytoskeleton and flagella of epimastigotes and colocalizes with acetylated α-tubulin in these structures. We have expressed TcATAT with an HA tag using the inducible vector pTcINDEX-GW in T. cruzi. Over-expression of TcATAT causes increased levels of the acetylated isoform, induces morphological and ultrastructural defects, especially in the mitochondrion, and causes a halt in the cell cycle progression of epimastigotes, which is related to an impairment of the kinetoplast division. Finally, as a result of TcATAT over-expression we observed that parasites became more resistant to microtubule depolymerizing drugs. These results support the idea that α-tubulin acetylation levels are finely regulated for the normal progression of T. cruzi cell cycle.
Three-color single-molecule imaging reveals conformational dynamics of dynein undergoing motility

Significance Dynein, a dimeric motor protein, moves along microtubules through adenosine 5′-triphosphate- and thermal-driven motions of two large ring domains (AAA rings) and small microtubule-binding domains (MTBDs) separated by a long coiled-coil. Previous single-molecule studies have tracked the positions of the AAA rings during motility, but not the MTBDs. Here, we tracked the relative positions of both MTBDs and one AAA ring by three-color, nanometer-resolution imaging. The observation of both MTBDs provided a direct measurement of how dynein steps on the tubulin subunits, and the simultaneous observation of three fiducial markers revealed extraordinary flexibility and previously unknown conformational states of the motor during motility. The techniques presented here can be used to explore conformational dynamics of many other macromolecular complexes. The motor protein dynein undergoes coordinated conformational changes of its domains during motility along microtubules. Previous single-molecule studies analyzed the motion of the AAA rings of the dynein homodimer, but not the distal microtubule-binding domains (MTBDs) that step along the track. Here, we simultaneously tracked with nanometer precision two MTBDs and one AAA ring of a single dynein as it underwent hundreds of steps using three-color imaging. We show that the AAA ring and the MTBDs do not always step simultaneously and can take differently sized steps. This variability in the movement between the AAA ring and MTBDs results in an unexpectedly large number of conformational states of dynein during motility. Extracting data on conformational transition biases, we could accurately model dynein stepping in silico. Our results reveal that the flexibility between major dynein domains is critical for dynein motility.
Combustion and leaching behavior of elements in the Argonne Premium Coal Samples

Eight Argonne Premium Coal samples and two other coal samples were used to observe the effects of combustion and leaching on 30 elements. The results were used to infer the modes of occurrence of these elements. Instrumental neutron activation analysis indicates that the effects of combustion and leaching on many elements varied markedly among the samples. As much as 90% of the selenium and bromine is volatilized from the bituminous coal samples, but substantially less is volatilized from the low-rank coals. We interpret the combustion and leaching behavior of these elements to indicate that they are associated with the organic fraction. Sodium, although nonvolatile, is ion-exchangeable in most samples, particularly in the low-rank coal samples where it is likely to be associated with the organic constituents. Potassium is primarily in an ion-exchangeable form in the Wyodak coal but is in HF-soluble phases (probably silicates) in most other samples. Cesium is in an unidentified HNO 3 -soluble phase in most samples. Virtually all the strontium and barium in the low-rank coal samples is removed by NH 4 OAc followed by HCl, indicating that these elements probably occur in both organic and inorganic phases. Most tungsten and tantalum are in insoluble phases, perhaps as oxides or in organic association. Hafnium is generally insoluble, but as much as 65% is HF soluble, perhaps due to the presence of very fine grained or metamict zircon. We interpret the leaching behavior of uranium to indicate its occurrence in chelates and its association with silicates and with zircon. Most of the rare-earth elements (REE) and thorium appear to be associated with phosphates. Differences in textural relationships may account for some of the differences in leaching behavior of the REE among samples. Zinc occurs predominantly in sphalerite. Either the remaining elements occur in several different modes of occurrence (scandium, iron), or the leaching data are equivocal (arsenic, antimon
Phospho-RNA sequencing with circAID-p-seq

Accurate positional information concerning ribosomes and RNA binding proteins with respect to their transcripts is important to understand the global regulatory network underlying protein and RNA fate in living cells. Most footprinting approaches generate RNA fragments bearing a phosphate or cyclic phosphate groups at their 3′ end. Unfortunately, all current protocols for library preparation rely only on the presence of a 3′ hydroxyl group. Here, we developed circAID-p-seq, a PCR-free library preparation for 3′ phospho-RNA sequencing. We applied circAID-p-seq to ribosome profiling, which produces fragments protected by ribosomes after endonuclease digestion. CircAID-p-seq, combined with the dedicated computational pipeline circAidMe, facilitates accurate, fast, highly efficient and low-cost sequencing of phospho-RNA fragments from eukaryotic cells and tissues. While assessing circAID-p-seq to portray ribosomes engaged with transcripts, we provide a versatile tool to unravel any 3′-phospho RNA molecules.
Differential role of type I and type II vestibular hair cells in two anti-gravity reflexes in the rat

1 Departament de Ciències Fisiològiques, Institut de Neurociènces, Universitat de Barcelona, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Catalunya, Spain 2 Institut d’Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L’Hospitalet de Llobregat, Catalunya, Spain. Corresponding autor: Prof. Jordi Llorens, Ph.D.; e-mail: jllorens@ub.edu; Ph: +34934024277 e-mail addresses and ORCID codes: A.F. M. : amaroto7@ub.edu ; 0000-0001-8265-4902 A.B. G. : abarrallo@ub.edu ; 0000-0003-2086-8926 J.L. : jllorens@ub.edu ; 0000-0002-3894-9401
Specialized coding patterns among dorsomedial prefrontal neuronal ensembles predict conditioned reward seeking

Non-overlapping cell populations within dorsomedial prefrontal cortex (dmPFC), defined by gene expression or projection target, control dissociable aspects of reward seeking through unique activity patterns. However, even within these defined cell populations, considerable cell-to-cell variability is found, suggesting that greater resolution is needed to understand information processing in dmPFC. Here, we use two-photon calcium imaging in awake, behaving mice to monitor the activity of dmPFC excitatory neurons throughout Pavlovian reward conditioning. We characterize five unique neuronal ensembles that each encodes specialized information related to a sucrose reward, reward-predictive cues, and behavioral responses to those cues. The ensembles differentially emerge across daily training sessions – and stabilize after learning – in a manner that improves the predictive validity of dmPFC activity dynamics for deciphering variables related to behavioral conditioning. Our results characterize the complex dmPFC neuronal ensemble dynamics that stably predict reward availability and initiation of conditioned reward seeking following cue-reward learning.
Sex‐specific associations between traumatic experiences and resting‐state functional connectivity in the Philadelphia Neurodevelopmental Cohort

Background Traumatic experiences during childhood or adolescence are a significant risk factor for multiple psychiatric disorders and adversely affect cognitive functions. Resting-state functional magnetic resonance imaging has been used to investigate the effects of traumatic experiences on functional connectivity, but the impact of sex differences has not been well documented. This study investigated sex-specific associations between resting-state functional connectivity and traumatic experiences in typically developing youth. Methods The sample comprised 1395 participants, ages 8 to 21 years, from the Philadelphia Neurodevelopmental Cohort. Resting-state functional connectivity was characterized by voxel-wise intrinsic connectivity distribution parameter values derived from resting-state functional magnetic resonance imaging. Traumatic experiences were assessed based on a structured psychiatric evaluation. Sex, the number of traumatic events, and their interaction were regressed onto voxel-wise intrinsic connectivity distribution parameter values. Brain regions that passed cluster correction were used as seeds to define resting-state networks. Results After quality control, the final sample included 914 participants (mean (SD) age, 14.6 (3.3) years; 529 (57.8%) females; 437 (47.8%) experienced at least one kind of traumatic event). Four discrete anatomical clusters showed decreased functional connectivity as the number of traumatic events increased. The resting-state networks defined by using these four clusters as seeds corresponded with the somatomotor network. Sex-specific associations were identified in another four clusters for which males showed increased connectivity, and females showed decreased connectivity as the number of traumatic events increased. The resting-state networks defined by the four sex-specific clusters corresponded with the default mode network. Conclusions Traumatic experiences are associated with an alteration of resting-state functional connectivity in the somatomotor network in youth without psychiatric diagnoses. The associations differ in direction between males and females in the default mode network, suggesting sex-specific responses to early exposure to trauma.
Large-scale simulations of biological cell sorting driven by differential adhesion follow diffusion-limited domain coalescence regime

Cell sorting, whereby a heterogeneous cell mixture segregates and forms distinct homogeneous tissues, is one of the main collective cell behaviors at work during development. Although differences in interfacial energies are recognized to be a possible driving source for cell sorting, no clear consensus has emerged on the kinetic law of cell sorting driven by differential adhesion. Using a modified Cellular Potts Model algorithm that allows for efficient simulations while preserving the connectivity of cells, we numerically explore cell-sorting dynamics over unprecedentedly large scales in space and time. For a binary mixture of cells surrounded by a medium, increase of domain size follows a power-law with exponent n = 1/4 independently of the mixture ratio, revealing that the kinetics is dominated by the diffusion and coalescence of rounded domains. We compare these results with recent numerical and experimental studies on cell sorting, and discuss the importance of boundary conditions, space dimension, initial cluster geometry, and finite size effects on the observed scaling. Author summary Cell sorting describes the spontaneous segregation of identical cells in biological tissues. This phenomenon is observed during development or organ regeneration in a variety of biological systems. Minimization of the total surface energy of a tissue, in which adhesion strengh between homotypic and heterotypic cells are different, is one of the mechanisms that explain cell sorting. This mechanism is then similar to the one that drives demixing of two immiscible fluids. Because of the high sensibility of this process to finite-size and finite-time effects, no clear consensus has emerged on the scaling law of cell sorting driven by differential adhesion. Using an efficient numerical code, we were able to investigate this scaling law on very large binary mixtures of cells. We show that on long times, cell sorting obeys a universal power law, which is independent of the mixture ratio.
IFT88 transports Gucy2d, a guanylyl cyclase, to maintain sensory cilia function in Drosophila

Cilia are involved in a plethora of motility and sensory-related functions. Ciliary defects cause several ciliopathies, some of which with late-onset, suggesting cilia are actively maintained. While much is known about cilia assembly, little is understood about the mechanisms of their maintenance. Given that intraflagellar transport (IFT) is essential for cilium assembly, we investigated the role of one of its main players, IFT88, in ciliary maintenance. We show that DmIFT88, the Drosophila melanogaster orthologue of IFT88, continues to move along fully formed sensory cilia, and that its acute knockdown in the ciliated neurons of the adult affects sensory behaviour. We further identify DmGucy2d, the Drosophila guanylyl cyclase 2d, as a DmIFT88 cargo, whose loss also leads to defects in sensory behaviour maintenance. DmIFT88 binds to the intracellular part of DmGucy2d, which is evolutionarily conserved and mutated in several degenerative retina diseases, taking the cyclase into the cilia. Our results offer a novel mechanism for the maintenance of sensory cilia function and its potential role in human diseases.
Uniaxial Drawing of Isotactic Poly(acrylonitrile): Development of Oriented Structure and Tensile Properties

Uniaxial drawing of isotactic poly(acrylonitrile) (iso-PAN, isotactic triad fraction of 68%) and the resultant structure and tensile properties of drawn products were studied. The results were compared to those of atactic-PAN (at-PAN). Dried gel films prepared from 2 to 10 wt % solutions in N,N‘-dimethylformamide were initially drawn by solid-state coextrusion (first-stage draw) to an extrusion draw ratio of 16, followed by a further tensile draw at 100−200 °C (second-stage draw). The ductility of iso-PAN increased rapidly above 100 °C, due to the onset of molecular motion in crystalline regions, as found by WAXD at elevated temperatures. In contrast, the ductility of at-PAN increased above the first-order crystal/crystal transition at around 150 °C. Thus, the temperature for optimum second-stage draw of iso-PAN, 130−140 °C, was significantly lower than that (160−180 °C) of at-PAN, reflecting their crystal softening temperatures. The maximum achieved total draw ratios (DRt), after the two-stage draw, were.
Neural network aided approximation and parameter inference of stochastic models of gene expression

Non-Markov models of stochastic biochemical kinetics often incorporate explicit time delays to effectively model large numbers of intermediate biochemical processes. Analysis and simulation of these models, as well as the inference of their parameters from data, are fraught with difficulties because the dynamics depends on the system’s history. Here we use an artificial neural network to approximate the time-dependent distributions of non-Markov models by the solutions of much simpler time-inhomogeneous Markov models; the approximation does not increase the dimensionality of the model and simultaneously leads to inference of the kinetic parameters. The training of the neural network uses a relatively small set of noisy measurements generated by experimental data or stochastic simulations of the non-Markov model. We show using a variety of models, where the delays stem from transcriptional processes and feedback control, that the Markov models learnt by the neural network accurately reflect the stochastic dynamics across parameter space.
High heritability of telomere length, but low evolvability, and no significant heritability of telomere shortening in wild jackdaws

Telomere length (TL) and shortening rate predict survival in many organisms. Evolutionary dynamics of TL in response to survival selection depend on the presence of genetic variation that selection can act upon. However, the amount of standing genetic variation is poorly known for both TL and TL shortening rate, and has not been studied for both traits in combination in a wild vertebrate. We used experimental (cross-fostering) and statistical (animal models) means to disentangle and estimate genetic and environmental contributions to TL variation in pedigreed free-living jackdaws (Corvus monedula). TL was measured twice early in life (age- and interval-standardized), when shortening is highest, using the high-precision TRF technique, adapted to exclude interstitial telomeric sequences. TL shortened significantly during the nestling phase (10.4 bp/day), was highly repeatable within individuals (R=0.97) and genetically correlated between the two ages (rG>0.99). Additive genetic effects explained the major part of TL variation between individuals, with heritability on average estimated at h2=0.74. Parent- offspring regressions yielded similar estimates for the sexes when accounting for changes in paternal TL over life. Cohort effects explained a small but significant part of TL variation. Heritable variation for telomere shortening was negligible. Despite the high heritability of TL, its evolvability, which scales the additive genetic variance by mean TL, was close to zero. Hence evolutionary change of TL is likely to be slow despite significant selection.