Miracle-dz/UniFAR-FTUs huggingface dataset:
A Learned Map for Places and Concepts in the Human Medial Temporal Lobe

Distinct lines of research in both humans and animals point to a specific role of the hippocampus in both spatial and episodic memory function. The discovery of concept cells in the hippocampus and surrounding medial temporal lobe (MTL) regions suggests that the MTL maps physical and semantic spaces with a similar neural architecture. Here, we studied the emergence of such maps using MTL microwire recordings from 20 patients (9 female, 11 male) navigating a virtual environment featuring salient landmarks with established semantic meaning. We present several key findings. The array of local field potentials in the MTL contains sufficient information for above-chance decoding of subjects ’ instantaneous location in the environment. Closer examination revealed that as subjects gain experience with the environment the field potentials come to represent both the subjects ’ locations in virtual space and in high-dimensional semantic space. Similarly, we observe a learning effect on temporal sequence coding. Over time, field potentials come to represent future locations, even after controlling for spatial proximity. This predictive coding of future states, more so than the strength of spatial representations per se, is linked to variability in subjects ’ navigation performance. Our results thus support the conceptualization of the MTL as a memory space, representing both spatial-and nonspatial information to plan future actions and predict their outcomes.
An Integral Approach to Affective Education

The author uses twelve AQAL dimensions of education as described by Sean Esbjorn-Hargens to approximate a “report card” for evaluating any curriculum with an affective focus. This completeness is not just an academic exercise but shows the practicality and advantage of an Integral approach in the real world. Four affective educational models will also be examined using Integral perspectives. The features of these programs will be measured using an example of an Integral assessment of their strengths, foci, and weaknesses.
Investigating the user experience of IDN based virtual reality environments for solving complex issues

ABSTRACT Interactive Digital Narratives (IDNs) have evolved as a medium to address complex societal challenges due to its integration in advance technologies such as VR. Recent research has shown that VR provides a suitable environment to implement IDNs allowing the end users to experience narratives in a systematic and participatory setting. However, research is needed to understand the perceived user experience of these narrative experiences. This research highlights the role of IDNs in VR designed for natural hazard risk mitigation and how it affects the perceived user experience. we present two case studies quantifying the user experience of an IDN-based emergency preparedness VR system for solving the complex issue of natural hazards. The results demonstrate how spatial presence, cognitive behaviour and engagement is positively influenced by incorporating IDNs in VR. The research is part of a project called World of Wild Waters (WoWW) and illustrates the importance of narrative representations in VREs showing that IDN can be considered an essential factor in shaping the positive experience of end-users.
Differential effects of acute exercise on emotional memory in men and women

Exercise may change emotional memory, which is associated with the induction of mental disorders such as depression and anxiety. This effect of exercise may be influenced by exercise-induced cortisol release. Depending on sex, cortisol exerts differential effects on emotional memory consolidation. However, whether acute exercise and exercise-induced cortisol release have sex-dependent effects on emotional memory has not been established. Therefore, first, we aimed to determine the effects of acute exercise on emotional memory, separately for men and women, in a within-subjects design. Second, we aimed to examine whether the effects of acute exercise on emotional memory are related to the effects of exercise-induced cortisol release, separately for men and women. Sixteen healthy men and 15 healthy women were presented with positive and negative emotional images, followed by either rest or a vigorous-intensity cycling exercise condition using a within-subjects design on separate days. Salivary cortisol was measured before presenting the emotional images presentation and 20 min after each intervention. Emotional memory was assessed two days later. Vigorous-intensity exercise decreased emotional memory in women, whereas there was no change in men after rest or exercise. Cortisol levels increased after exercise intervention in both men and women, although there was no association between cortisol levels and emotional memory. These findings demonstrate that the effect of a single bout of vigorous-intensity exercise on emotional memory differs between men and women and is associated with decreased emotional memory in women.
Insights from a genome-wide truth set of tandem repeat variation

Tools for genotyping tandem repeats (TRs) from short read sequencing data have improved significantly over the past decade. Extensive comparisons of these tools to gold standard diagnostic methods like RP-PCR have confirmed their accuracy for tens to hundreds of well-studied loci. However, a scarcity of high-quality orthogonal truth data limited our ability to measure tool accuracy for the millions of other loci throughout the genome. To address this, we developed a TR truth set based on the Synthetic Diploid Benchmark (SynDip). By identifying the subset of insertions and deletions that represent TR expansions or contractions with motifs between 2 and 50 base pairs, we obtained accurate genotypes for 139,795 pure and 6,845 interrupted repeats in a single diploid sample. Our approach did not require running existing genotyping tools on short read or long read sequencing data and provided an alternative, more accurate view of tandem repeat variation. We applied this truth set to compare the strengths and weaknesses of widely-used tools for genotyping TRs, evaluated the completeness of existing genome-wide TR catalogs, and explored the properties of tandem repeat variation throughout the genome. We found that, without filtering, ExpansionHunter had higher accuracy than GangSTR and HipSTR over a wide range of motifs and allele sizes. Also, when errors in allele size occurred, ExpansionHunter tended to overestimate expansion sizes, while GangSTR tended to underestimate them. Additionally, we saw that widely-used TR catalogs miss between 16% and 41% of variant loci in the truth set. These results suggest that genome-wide analyses would benefit from genotyping a larger set of loci as well as further tool development that builds on the strengths of current algorithms. To that end, we developed a new catalog of 2.8 million loci that captures 95% of variant loci in the truth set, and created a modified version of ExpansionHunter that runs 2 to 3x faster than the original while producing the same output.
Measurement of Broadband Diffuse Solar Irradiance Using Current Commercial Instrumentation with a Correction for Thermal Offset Errors

Abstract Diffuse-sky solar irradiance is an important quantity for radiation budget research, particularly as it relates to climate. Diffuse irradiance is one component of the total downwelling solar irradiance and contains information on the amount of downward-scattered, as opposed to directly transmitted, solar radiation. Additionally, the diffuse component is often required when calibrating total irradiance radiometers. A variety of pyranometers are commonly used to measure solar diffuse irradiance. An examination of some instruments for measuring diffuse irradiance using solar tracking shade disks is presented, along with an evaluation of the achieved accuracy. A data correction procedure that is intended to account for the offset caused by thermal IR exchange between the detector and filter domes in certain common diffuse pyranometers is developed and validated. The correction factor is derived from outputs of a collocated pyrgeometer that measures atmospheric infrared irradiance.
Ice Formation by Sulfate and Sulfuric Acid Aerosol Particles under Upper-Tropospheric Conditions

Abstract Ice formation in ammoniated sulfate and sulfuric acid aerosol particles under upper-tropospheric conditions was studied using a continuous flow thermal diffusion chamber. This technique allowed for particle exposure to controlled temperatures and relative humidities for known residence times. The phase states of (NH4)2SO4 and NH4HSO4 particles were found to have important impacts on their ice formation capabilities. Dry (NH4)2SO4 particles nucleated ice only at high relative humidity (RH ≥ 94%) with respect to water at temperatures between −40° and −60°C. This result suggested either an impedance or finite time dependence to deliquescence and subsequent homogeneous freezing nucleation. Ammonium sulfate particles that entered the diffusion chamber in a liquid state froze homogeneously at relative humidities that were 10% lower than where ice nucleated on initially dry particles. Likewise, crystalline or partially crystallized (as letovicite) NH4HSO4 particles required higher relative humidities fo.
The Mechanical Influence of Densification on Initial Epithelial Architecture

Epithelial tissues are the most abundant tissue type in animals, lining body cavities and generating compartment barriers. The function of a monolayer epithelium – whether protective, secretory, absorptive, or filtrative –relies on regular tissue architecture with respect to the apical-basal axis. Using an unbiased 3D analysis pipeline developed in our lab, we previously showed that epithelial tissue architectures in culture can be divided into distinct developmental categories, and that these are intimately connected to cell density: at sparse densities, cultured epithelial cell layers have a squamous morphology (Immature); at intermediate densities, these layers develop lateral cell-cell borders and rounded cell apices (Intermediate); cells at the highest densities reach their full height and demonstrate flattened apices (Mature). These observations prompted us to ask whether epithelial architecture emerges from the mechanical constraints of densification, and to what extent a hallmark feature of epithelial cells, namely cell-cell adhesion, contributes. In other words, to what extent is the shape of cells in an epithelial layer a simple matter of sticky, deformable objects squeezing together? We addressed this problem using a combination of computational modeling and experimental manipulations. Our results show that the first morphological transition, from Immature to Intermediate, can be explained simply by cell crowding. Additionally, we identify a new division (and thus transition) within the Intermediate category, and find that this second morphology relies on cell-cell adhesion.
Elevated HIV viral load is associated with higher recombination rate in vivo

HIV’s exceptionally high recombination rate drives its intra-host diversification, enabling immune escape and multi-drug resistance within people living with HIV. While we know that HIV’s recombination rate varies by genomic position, we have little understanding of how recombination varies throughout infection or between individuals as a function of the rate of cellular coinfection. We hypothesize that denser intra-host populations may have higher rates of coinfection and therefore recombination. To test this hypothesis, we develop a new approach (Recombination Analysis via Time Series Linkage Decay, or RATS-LD) to quantify recombination using autocorrelation of linkage between mutations across time points. We validate RATS-LD on simulated data under short read sequencing conditions and then apply it to longitudinal, high-throughput intra-host viral sequencing data, stratifying populations by viral load (a proxy for density). Among sampled viral populations with the lowest viral loads (< 26,800 copies/mL), we estimate a recombination rate of 1.5×10−5 events/bp/generation (95% CI: 7×10−6−2.9×10−5), similar to existing estimates. However, among samples with the highest viral loads (> 82,000 copies/mL), our median estimate is approximately 6 times higher. In addition to co-varying across individuals, we also find that recombination rate and viral load are associated within single individuals across different time points. Our findings suggest that rather than acting as a constant, uniform force, recombination can vary dynamically and drastically across intra-host viral populations and within them over time. More broadly, we hypothesize that this phenomenon may affect other facultatively asexual populations where spatial co-localization varies.
tRNASer overexpression induces adaptive mutations in NSCLC tumors

tRNAs are a driving force of genome evolution in Yeast and Bacteria. Their deregulation is frequently observed in tumors with Serine tRNAs being often overexpressed. This has important functional consequences, such as increased metabolism and tumor growth. In yeast, time and chemical stimulus boost alterations in the genome driven by tRNA deregulation. Therefore, we hypothesized that tRNA deregulation may contribute to the increased genome instability observed in tumors. To study the effect of tRNA deregulation in tumors, we overexpressed tRNA-Ser-AGA-2-1 in a NSCLC cell line, H460. This cell line and a Mock (control) were xenografted in nude mice and collected at 3 timepoints: T1-Naïve; T2-Treated once with cisplatin/vehicle and; T3) treated twice with cisplatin/vehicle. These tumors were characterized by WES, RNAseq and Mass Spectrometry and the data obtained was integrated. The tumor mutation burden was increased in T3 tRNASerOE tumors, regardless of treatment. Although in T1 Mock and tRNASer tumors have a similar number of variants, in T2&3, tRNASerOE tumors display two times more variants than Mock tumors regardless of treatment. Interestingly, tRNASerOE exclusive variants favor proliferation and therapy resistance, which is in line with the phenotypes observed and supported by RNAseq and proteomics data. In conclusion, tRNASerOE increases the tumor mutation burden and the variants detected favor tumor growth, proving tRNA deregulation is enough to induce adaptive mutations in the genome.
A single-cell strategy for the identification of intronic variants related to mis-splicing in pancreatic cancer

Most clinical diagnostic and genomic research setups focus almost exclusively on coding regions and essential splice sites, thereby overlooking other non-coding variants. As a result, intronic variants that can promote mis-splicing events across a range of diseases, including cancer, are yet to be systematically investigated. Such investigations would require both genomic and transcriptomic data, but there currently exist very few datasets that satisfy these requirements. We address this by developing a single-nucleus full-length RNA-sequencing approach that allows for the detection of potentially pathogenic intronic variants. We exemplify the potency of our approach by applying pancreatic cancer tumor and tumor-derived specimens and linking intronic variants to splicing dysregulation. We specifically find that prominent intron retention and pseudo-exon activation events are shared by the tumors and affect genes encoding key transcriptional regulators. Our work paves the way for the assessment and exploitation of intronic mutations as powerful prognostic markers and potential therapeutic targets in cancer. Graphical Abstract
Exploring natural odour landscapes: A case study with implications for human-biting insects

The natural world is full of odours—blends of volatile chemicals emitted by potential sources of food, social partners, predators, and pathogens. Animals rely heavily on these signals for survival and reproduction. Yet we remain remarkably ignorant of the composition of the chemical world. How many compounds do natural odours typically contain? How often are those compounds shared across stimuli? What are the best statistical strategies for discrimination? Answering these questions will deliver crucial insight into how brains can most efficiently encode olfactory information. Here, we undertake the first large-scale survey of vertebrate body odours, a set of stimuli relevant to blood- feeding arthropods. We quantitatively characterize the odour of 64 vertebrate species (mostly mammals), representing 29 families and 13 orders. We confirm that these stimuli are complex blends of relatively common, shared compounds and show that they are much less likely to contain unique components than are floral odours—a finding with implications for olfactory coding in blood feeders and floral visitors. We also find that vertebrate body odours carry little phylogenetic information, yet show consistency within a species. Human odour is especially unique, even compared to the odour of other great apes. Finally, we use our newfound understanding of odour-space statistics to make specific predictions about olfactory coding, which align with known features of mosquito olfactory systems. Our work provides one of the first quantitative descriptions of a natural odour space and demonstrates how understanding the statistics of sensory environments can provide novel insight into sensory coding and evolution.
RNA polymerase II pausing is essential during spermatogenesis for appropriate gene expression and completion of meiosis

Male germ cell development requires precise regulation of gene activity in a cell-type and stage-specific manner, with perturbations in gene expression during spermatogenesis associated with infertility. Here, we use steady-state, nascent and single-cell RNA sequencing strategies to comprehensively characterize gene expression across male germ cell populations, to dissect the mechanisms of gene control and provide new insights towards therapy. We discover a requirement for pausing of RNA Polymerase II (Pol II) at the earliest stages of sperm differentiation to establish the landscape of gene activity across development. Accordingly, genetic knockout of the Pol II pause-inducing factor NELF in immature germ cells blocks differentiation to mature spermatids. Further, we uncover unanticipated roles for Pol II pausing in the regulation of meiosis during spermatogenesis, with the presence of paused Pol II associated with double strand break formation by SPO11, and disruption of SPO11 expression in germ cells lacking NELF.
Introgression of a dominant phototropin1 mutant superenhances carotenoids and boosts flavor-related volatiles in genome-edited tomato RIN mutants

The tomato (Solanum lycopersicum) ripening inhibitor (rin) mutation is known to completely repress fruit ripening. The heterozygous (RIN/rin) fruits have extended shelf life, ripen normally, but have poor taste and flavour. Even the CRISPR/Cas9-generated rin alleles have these undesirable attributes associated with the rin mutation. To address this, we used genome editing to generate newer alleles of RIN (rinCR) by targeting the K domain, which is essential for the oligomerization of MADS-box transcription factors. Unlike previously reported CRISPR alleles, the rinCRalleles displayed delayed onset of ripening, suggesting that the mutated K domain represses the onset of ripening. The rinCR fruits had extended shelf life and accumulated carotenoids at an intermediate level between rin and wild-type parent. Besides, the metabolites and hormonal levels in rinCR fruits were more akin to rin. To overcome the negative attributes of rin, we crossed the rinCR alleles with Nps1, which enhances carotenoid levels in tomato fruits. Nps1 harbours a dominant-negative mutation in the plant photoreceptor phototropin1. The resulting Nps1/rinCR hybrids had extended shelf life and 4.4-7.1-fold higher carotenoid levels than the wild-type parent. The Nps1/rinCR fruits had higher auxin and reduced ABA levels, which are reportedly linked with slower ripening. The metabolome of Nps1/rinCRfruits revealed higher sucrose, malate, and volatiles associated with tomato taste and flavour. Notably, the boosted volatile levels in Nps1/rinCR were only observed in fruits bearing the homozygous Nps1 (Nps1/Nps1) mutation. Our findings suggest that the Nps1 introgression into tomato ripening mutants provides a promising strategy for developing tomato cultivars with extended shelf life, improved taste, and flavour.
A riboswitch-controlled manganese exporter (Alx) tunes intracellular Mn2+ concentration in E. coli at alkaline pH

Cells use transition metal ions as structural components of biomolecules and cofactors in enzymatic reactions, making transition metals vital cellular components. The buildup of a particular metal ion in certain stress conditions becomes harmful to the organism due to the misincorporation of the excess ion into biomolecules, resulting in perturbed enzymatic activity or metal-catalyzed formation of reactive oxygen species. Organisms optimize metal concentration by regulating the expression of proteins that import and export that metal, often in a metal concentration-dependent manner. One such regulation mechanism is via riboswitches, which are 5’-untranslated regions (UTR) of an mRNA that undergo conformational changes to promote or inhibit the expression of the downstream gene, commonly in response to a ligand. The yybP-ykoY family of bacterial riboswitches shares a conserved aptamer domain that binds manganese (Mn2+). In E. coli, the yybP-ykoY riboswitch precedes and regulates the expression of two genes: mntP, which based on extensive genetic evidence encodes an Mn2+ exporter, and alx, which encodes a putative metal ion transporter whose cognate ligand is currently in question. Expression of alx is upregulated by both elevated intracellular concentrations of Mn2+ and alkaline pH. With metal ion measurements and gene expression studies, we demonstrate that the alkalinization of media increases cytoplasmic Mn2+ content, which in turn enhances alx expression. Alx then exports excess Mn2+ to prevent toxic buildup of the metal inside the cell, with the export activity maximal at alkaline pH. Using mutational and complementation experiments, we pinpoint a set of acidic residues in the predicted transmembrane segments of Alx that play a crucial role in its Mn2+ export. We propose that Alx-mediated Mn2+ export provides a primary protective layer that fine-tunes the cytoplasmic Mn2+ levels, especially during alkaline stress.
Cardiomyopathy-Associated Variants Alter the Structure and Function of the α-Actinin-2 Actin-Binding Domain

Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM) are characterized by thickening, thinning, or stiffening, respectively, of the ventricular myocardium, resulting in diastolic or systolic dysfunction that can lead to heart failure and sudden cardiac death. Recently, variants in the ACTN2 gene, encoding the protein α-actinin-2, have been reported in HCM, DCM, and RCM patients. However, functional data supporting the pathogenicity of these variants is limited, and potential mechanisms by which these variants cause disease are largely unexplored. Currently, NIH ClinVar lists 34 ACTN2 missense variants, identified in cardiomyopathy patients, which we predict are likely to disrupt actin binding, based on their localization to specific substructures in the α-actinin-2 actin binding domain (ABD). We investigated the molecular consequences of three ABD localized, HCM-associated variants: A119T, M228T and T247M. Using circular dichroism, we demonstrate that the mutant ABD proteins can attain a well-folded state. However, thermal denaturation studies show that all three mutations are destabilizing, suggesting a structural disruption. Importantly, A119T decreased actin binding, and M228T and T247M cause increased actin binding. We suggest that altered actin binding underlies pathogenesis for cardiomyopathy mutations localizing to the ABD of α-actinin-2.