Miracle-dz/UniFAR-FTUs huggingface dataset:
How families design and program games: a qualitative analysis of a 4-week online in-home study

Prior work has broadly explored empowering children to learn to program by making video games. However, such work has rarely considered the role of families in this learning, leaving many open questions about how inter-generational collaborations might support and constrain learning. To investigate these opportunities, we conducted a family-based study of TileCode, a rule-based programming platform for video-game programming, and scaffolded a 4-week series of game programming activities with 19 children (9 to 14 years old) and 16 parents. Using a joint media engagement lens to analyze family knowledge and programming strategies, we found: 1) families demonstrated many dynamic collaboration patterns distinct from pair programming and other collaboration models, 2) parents played a unique role in scaffolding and guiding more complex designs and programming tasks, 3) families found it challenging to start their games from scratch but benefited greatly from having programming patterns for particular game behaviors. These findings suggest the need for game programming platforms to design around the unique kinds of collaboration in inter-generational domain-specific programming.
Genome-Wide Identiﬁcation of Genes Expressed in Arabidopsis Pistils Speciﬁcally along the Path of Pollen Tube Growth 1[w]

Plant reproductive development is dependent on successful pollen-pistil interactions. In crucifers, the pollen tube must breach the stigma surface and burrow through the extracellular matrix of the stigma epidermal cells and transmitting tract cells before reaching its ovule targets. The high degree of speciﬁcity in pollen-pistil interactions and the precision of directional pollen tube growth suggest that signals are continually being exchanged between pollen/pollen tubes and cells of the pistil that line their path. However, with few exceptions, little is known about the genes that control these interactions. The specialized functions of stigma epidermal cells and transmitting tract cells are likely to depend on the activity of genes expressed speciﬁcally in these cells. In order to identify these genes, we used the Arabidopsis ( Arabidopsis thaliana ) ATH1 microarray to compare the whole- genome transcriptional proﬁles of stigmas and ovaries isolated from wild-type Arabidopsis and from transgenic plants in which cells of the stigma epidermis and transmitting tract were speciﬁcally ablated by expression of a cellular toxin. Among the 23,000 genes represented on the array, we identiﬁed 115 and 34 genes predicted to be expressed speciﬁcally in the stigma epidermis and transmitting tract, respectively. Both gene sets were signiﬁcantly enriched in predicted secreted proteins, including potential signaling components and proteins that might contribute to reinforcing, modifying, or remodeling the structure of the extracellular matrix during pollination. The possible role of these genes in compatible and incompatible pollen- pistil interactions is discussed. wild-type hybridization allowed to proceed for least 16 Hybridization conditions, posthybridiza- tion washes, and visualization and analysis of hybridization patterns were as described for RNA gel-blot analysis. Hybridization signals were normalized using b -tubulin4.
Identification of a compound which disrupts binding of amyloid-beta to the prion protein using a novel fluorescence-based assay

Background: The cellular form of the prion protein (PrP C ) is implicated in Alzheimer’s disease as a receptor for amyloid-beta (Aβ) Results: An assay was developed capable of identifying inhibitors of Aβ binding to PrP C Conclusion: Chicago Sky Blue inhibits Aβ binding to PrP C Significance: This is the first small molecule shown to disrupt the binding of Aβ to PrP C Abstract The prion protein (PrP) 4 has been implicated both in prion diseases such as Creutzfeldt-Jakob disease (CJD), where its monomeric cellular isoform (PrP C ) is recruited into pathogenic self-propagating polymers of misfolded protein, and in Alzheimer’s disease (AD) where PrP C may act as a receptor for synaptotoxic oligomeric forms of amyloid beta (Aβ). There has been considerable interest in identification of compounds which bind to PrP C , stabilising its native fold and thereby acting as pharmacological chaperones to block prion propagation and pathogenesis. However, compounds binding PrP C could also inhibit the binding of toxic Aβ species and may have a role in treating AD, a highly prevalent dementia for which there are currently no disease-modifying treatments. However, the absence of a unitary, readily measurable, physiological function of PrP makes screening for ligands challenging, and the highly heterogeneous nature of Aβ oligomer preparations makes conventional competition binding assays difficult to interpret. We have therefore developed a high-throughput screen which utilises site-specifically fluorescently labelled protein to identify compounds which bind to PrP and inhibit both Aβ binding and prion propagation. Following a screen of 1,200 approved drugs we identified Chicago Sky Blue 6B as the first small molecule PrP ligand capable of inhibiting Aβ binding, demonstrating the feasibility of development of drugs to block this interaction. The interaction of Chicago Sky Blue 6B was characterised by isothermal titration calorimetry and its ability to inhibit Aβ binding and reduce prion levels established in cell-based assays .
Australian cyclones and air-sea feedbacks

The importance of resolving mesoscale air-sea interactions to represent cyclones impacting the East Coast of Australia, the so-called East Coast Lows (ECLs), is investigated using the Australian Regional Coupled Model based on NEMO-OASIS-WRF (NOW) at 1/4◦ resolution. The fully coupled model is shown to be capable of reproducing correctly relevant features such as the seasonality, spatial distribution and intensity of ECLs while it partially resolves mesoscale processes, such as air-sea feedbacks over ocean eddies and fronts. The mesoscale thermal feedback (TFB) and the current feedback (CFB) are shown to influence the intensity of northern ECLs (north of 30◦S), with the TFB modulating the pre-storm sea surface temperature by shifting ECL locations eastwards and the CFB modulating the wind stress. By fully uncoupling the atmospheric model of NOW, the intensity of northern ECLs is increased due to the absence of the cold wake that provides a negative feedback to the cyclone. The number of ECLs might also be affected by the air-sea feedbacks but large interannual variability hampers significant results with short term simulations. The TFB and CFB modify the climatology of sea surface temperature (mean and variability) but no direct link is found between these changes and those noticed in ECL properties. These results show that the representation of ECLs, mainly north of 30◦S, depend on how air-sea feedbacks are simulated. This is particularly important for atmospheric downscaling of climate projections as small-scale sea surface temperature interactions and the effects of ocean currents are not accounted for. Plain Language Summary Air-sea interactions occur at a variety of spatial scales, including those of the size of ocean eddies . Such interactions are partially resolved in the Australian Regional Coupled Model used to simulate the cyclones impacting the East Coast of Australia, the so-called East Coast Lows (ECLs). The effect of different feedbacks between the ocean and the atmosphere, including those due to mechanical and thermal exchanges over ocean eddies, are tested on the properties of ECLs. Significant effects are found on the intensity of ECLs north of 30◦S, with also potential effects on the number of ECLs. The airsea feedbacks modify the climatology of sea surface temperature, with no direct link to ECL changes. Such experiments eventually demonstrate that small-scale air-sea feedbacks may matter for representing current Australian climate and its change in the future.
Nose-Only Exposure to Cherry- and Tobacco-Flavored E-Cigarettes Induced Lung Inflammation in Mice in a Sex-Dependent Manner

Flavoring chemicals utilized in electronic nicotine delivery systems (ENDS) have been shown to result in an increase in cellular inflammation, meanwhile, the effects of fruit and tobacco flavors on lung inflammation by nose-only exposures to mice are relatively unknown. We hypothesized that C57BL/6J mice exposed to flavored e-cigarettes would result in an increase in lung inflammation. C57BL/6J mice were exposed to air, propylene glycol/vegetable glycerin (PG/VG), and e-liquids “Apple”, “Cherry”, “Strawberry”, “Wintergreen”, and “Smooth & Mild Tobacco”, for one hour per day for a three day exposure. Quantification of flavoring chemicals was measured by proton nuclear magnetic resonance spectroscopy (1H NMR), differential cell counts by flow cytometry, pro-inflammatory cytokines/chemokines by ELISA, and matrix metalloproteinase levels by western blot. Exposure to PG/VG, Apple, and Smooth & Mild Tobacco resulted in an increase in neutrophil cell count in lung bronchoalveolar lavage fluid (BALF). Strawberry exposure increased KC levels in BALF while in lung homogenate KC levels were increased in PG/VG, Cherry, and Smooth & Mild Tobacco exposure. Exposure to PG/VG and Cherry increased IL-6 levels and in all exposed mice there was a male-specific decrease in MCP-1 levels in lung homogenate. Mice exposed to PG/VG, Apple, Cherry, and Wintergreen resulted in an increase in MMP2 levels. Our results indicate that female mice exposed to cherry flavored e-liquids and male mice exposed to tobacco flavored e-liquids resulted in an increase in inflammation, while exposure to mint flavored e-liquids resulted in a decrease in inflammatory cytokine and an increase in tissue repair proteins. This study revealed that flavored-based e-cigarette exposure elicited sex-specific alterations in lung inflammation, with cherry flavors/benzaldehyde eliciting female-specific increases in inflammation. This highlights the toxicity of flavored chemicals and the further need for regulation of flavoring chemicals.
Distraction and cognitive control independently impact parietal and prefrontal response to pain

Previous studies found that distracting someone through a challenging activity leads to hypoalgesia, an effect mediated by parietal and prefrontal processes. Other studies suggest that challenging activities affect the ability to regulate one’s aching experiences, due to partially-common neural substrate between cognitive control and pain at the level the medial prefrontal cortex. We investigated effects of distraction and cognitive control on pain by delivering noxious stimulations during or after a Stroop paradigm (requiring high cognitive load) or a neutral condition. We found less intense and unpleasant subjective pain ratings during (compared to after) task execution. This hypoalgesia was associated with enhanced activity at the level of the dorsolateral prefrontal cortex and the posterior parietal cortex, which also showed negative connectivity with the insula. Furthermore, multivariate pattern analysis revealed that distraction altered the neural response to pain, by making it more similar to that associated with previous Stroop tasks. All these effects were independent of the nature of the task which, instead, led to a localized neural modulation around the anterior cingulate cortex. Overall, our study underscores the role played by two facets of human executive functions, which exert independent influence in the neural response of pain.
Cortical Ripples during NREM Sleep and Waking in Humans

Hippocampal ripples index the reconstruction of spatiotemporal neuronal firing patterns essential for the consolidation of memories in the cortex during non-rapid eye movement sleep (NREM). Recently, cortical ripples in humans have been shown to enfold the replay of neuron firing patterns during cued recall. Here, using intracranial recordings from 18 patients (12 female), we show that cortical ripples also occur during NREM in humans, with similar density, oscillation frequency (∼90 Hz), duration, and amplitude to waking. Ripples occurred in all cortical regions with similar characteristics, unrelated to putative hippocampal connectivity, and were less dense and robust in higher association areas. Putative pyramidal and interneuron spiking phase-locked to cortical ripples during NREM, with phase delays consistent with ripple generation through pyramidal–interneuron feedback. Cortical ripples were smaller in amplitude than hippocampal ripples but were similar in density, frequency, and duration. Cortical ripples during NREM typically occurred just before the upstate peak, often during spindles. Upstates and spindles have previously been associated with memory consolidation, and we found that cortical ripples grouped cofiring between units within the window of spike timing-dependent plasticity. Thus, human NREM cortical ripples are as follows: ubiquitous and stereotyped with a tightly focused oscillation frequency; similar to hippocampal ripples; associated with upstates and spindles; and associated with unit cofiring. These properties are consistent with cortical ripples possibly contributing to memory consolidation and other functions during NREM in humans. SIGNIFICANCE STATEMENT In rodents, hippocampal ripples organize replay during sleep to promote memory consolidation in the cortex, where ripples also occur. However, evidence for cortical ripples in human sleep is limited, and their anatomic distribution and physiological properties are unexplored. Here, using human intracranial recordings, we demonstrate that ripples occur throughout the cortex during waking and sleep with highly stereotyped characteristics. During sleep, cortical ripples tend to occur during spindles on the down-to-upstate transition, and thus participate in a sequence of sleep waves that is important for consolidation. Furthermore, cortical ripples organize single-unit spiking with timing optimal to facilitate plasticity. Therefore, cortical ripples in humans possess essential physiological properties to support memory and other cognitive functions.
Methylation status of VTRNA2-1/nc886 is stable across human populations, monozygotic twin pairs and in majority of somatic tissues

Aims and methods Our aim was to characterise the methylation level of a polymorphically imprinted gene, VTRNA2-1/nc886, in human populations and somatic tissues. We utilised 48 datasets, consisting of >30 different tissues and >30 000 individuals. Results We show that the nc886 methylation status is associated with twin status and ethnic background, but the variation between populations is limited. Monozygotic twin pairs present concordant methylation, while ∼30% of dizygotic twin pairs present discordant methylation in the nc886 locus. The methylation levels of nc886 are uniform across somatic tissues, except in cerebellum and skeletal muscle. Conclusion We hypothesize that the nc886 imprint is established in the oocyte and that after implantation, the methylation status is stable, excluding a few specific tissues.
Trajectories for the evolution of bacterial CO2-concentrating mechanisms

Significance The emergence of biological novelty is often coupled to the evolution of Earth’s chemical environment. Here, we studied how the evolution of a bacterial CO2-concentrating mechanism (CCM)—a complex, multicomponent system that enables modern CO2-fixing bacteria to grow robustly in environments with low CO2—depends on environmental CO2 levels. Using a “synthetic biological” approach to assay the growth of the present-day bacteria engineered to resemble ancient ones, we show that it is possible to explain the emergence of bacterial CCMs if atmospheric CO2 was once much higher than today, consistent with geochemical proxies. Taken together, our results delineated an unexpected “CO2-catalyzed” pathway for the evolution of bacterial CCMs, whose multiple emergence has been challenging to understand.
Resource-rational account of sequential effects in human prediction

An abundant literature reports on ‘sequential effects’ observed when humans make predictions on the basis of stochastic sequences of stimuli. Such sequential effects represent departures from an optimal, Bayesian process. A prominent explanation posits that humans are adapted to changing environments, and erroneously assume nonstationarity of the environment, even if the latter is static. As a result, their predictions fluctuate over time. We propose a different explanation in which sub-optimal and fluctuating predictions result from cognitive constraints (or costs), under which humans however behave rationally. We devise a framework of costly inference, in which we develop two classes of models that differ by the nature of the constraints at play: in one case the precision of beliefs comes at a cost, resulting in an exponential forgetting of past observations, while in the other beliefs with high predictive power are favored. To compare model predictions to human behavior, we carry out a prediction task that uses binary random stimuli, with probabilities ranging from . 05 to . 95. Although in this task the environment is static and the Bayesian belief converges, subjects’ predictions fluctuate and are biased toward the recent stimulus history. Both classes of models capture this ‘attractive effect’, but they depart in their characterization of higher-order effects. Only the precision-cost model reproduces a ‘repulsive effect’, observed in the data, in which predictions are biased away from stimuli presented in more distant trials. Our experimental results reveal systematic modulations in sequential effects, which our theoretical approach accounts for in terms of rationality under cognitive constraints.
Non-catastrophic collapse of VEEV by lethal mutagenesis

RNA viruses replicate at a high mutation rate, providing a highly adaptive capacity to the population as well as vulnerability to an extinction due to additional mutations, which is the conceptual basis for lethal mutagenesis. However, the mechanistic understanding of lethal mutagenesis has remained unclear due to the lack of RNA mutagens with potent antiviral activity and the inherent inability to distinguish between infectious and non-infectious sub-populations within a viral population. In our study, we investigated how the replication competency and mutation frequency of Venezuelan Equine Encephalitis Virus (VEEV) change following treatment with the RNA mutagen β-d-N4-hydroxycytidine, a potent antiviral RNA mutagen. By pairing limiting dilution with a long-read sequencing approach, we specifically determined genomic sequences of replication-competent viral clones from the total population. We found that replication-competent VEEV population maintained itself within a narrow mutation spectrum with a significantly lower mutation frequency than the total population. We also found that treatment with an RNA mutagen did not induce catastrophic destruction of the infectious population even at a high exposure, allowing replication-competent subpopulations with increased variability in mutational fitness and enhanced adaptability to new selection pressures, such as antiviral treatment, to continue to propagate. Together our study provides new understanding of viral population landscape and suggests a careful consideration of lethal mutagenesis as an antiviral strategy for high-capacity replicating viruses such as alphaviruses.
The unfolded protein response transcription factor XBP1s ameliorates Alzheimer’s disease by improving synaptic function and proteostasis

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer’s disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). A polymorphism in the XBP1 promoter has been suggested as a risk factor for AD. To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in neurons using preclinical models. Overexpression of an active form of XBP1 in the nervous system using transgenic mice significantly reduced the load of amyloid deposits in the cerebral cortex and hippocampus and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved long-term potentiation, memory performance, and dendritic spine density. Quantitative proteomics of the hippocampus revealed that XBP1 expression corrects a large proportion of the alterations observed in the 5xFAD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.
Hippocampal 4-Hz oscillations emerge during stationary running in a wheel and are resistant to medial septum inactivation

Recent studies described 2-4 Hz oscillations in the hippocampus of rats performing stationary locomotion on treadmills and other apparatus. Since the 2-4 Hz rhythm shares common features with hippocampal theta (5-12 Hz) oscillations - such as a positive running speed-amplitude relationship and modulation of spiking activity - many have questioned whether these rhythms are related or independently generated. To answer this question, we analyzed local field potentials (LFP) and spiking activity from the dorsal CA1 of rats executing a spatial alternation task and running for ∼15 s in a wheel during the intertrial intervals both before and after muscimol injection into the medial septum. We observed 4-Hz oscillations during wheel runs, but not during maze runs. The 4-Hz amplitude positively correlated with wheel speed and negatively with maze speed. Also, the amplitude of 4-Hz and theta oscillations were inversely related. Medial septum inactivation abolished hippocampal theta but preserved 4-Hz oscillations. It also affected the entrainment of pyramidal cells and interneurons by 4-Hz rhythmic activity. In all, these results dissociate the underlying mechanism of 4-Hz and theta oscillations in the rat hippocampus. Highlights 4-Hz oscillations emerge in the rat hippocampus during wheel running and correlate with speed 4-Hz and theta amplitude are inversely correlated 4-Hz oscillations are resistant to medial septum inactivation Rhythmic discharge of interneurons and pyramidal cells at 4-Hz are reduced by medial septum inactivation In brief Lima and Belchior tested whether the pharmacological inactivation of the medial septum affects hippocampal 4-Hz oscillations associated with stationary running. They found that septal inactivation preserved 4-Hz oscillations while abolished theta, which dissociate the underlying mechanisms of these rhythms in the rat hippocampus.