Miracle-dz/UniFAR-FTUs huggingface dataset:
PD-1 inhibits T cell actin remodeling at the immunological synapse independently of its signaling motifs

Engagement of the receptor programmed cell death molecule 1 (PD-1) by its ligands PD-L1 and PD-L2 inhibits T cell–mediated immune responses. Blocking such signaling provides the clinical effects of PD-1–targeted immunotherapy. Here, we investigated the mechanisms underlying PD-1–mediated inhibition. Because dynamic actin remodeling is crucial for T cell functions, we characterized the effects of PD-1 engagement on actin remodeling at the immunological synapse, the interface between a T cell and an antigen-presenting cell (APC) or target cell. We used microscopy to analyze the formation of immunological synapses between PD-1+ Jurkat cells or primary human CD8+ cytotoxic T cells and APCs that presented T cell–activating antibodies and were either positive or negative for PD-L1. PD-1 binding to PD-L1 inhibited T cell spreading induced by antibody-mediated activation, which was characterized by the absence of the F-actin–dense distal lamellipodial network at the immunological synapse and the Arp2/3 complex, which mediates branched actin formation. PD-1–induced inhibition of actin remodeling also prevented the characteristic deformation of T cells that contact APCs and the release of cytotoxic granules. We showed that the effects of PD-1 on actin remodeling did not require its tyrosine-based signaling motifs, which are thought to mediate the co-inhibitory effects of PD-1. Our study highlights a previously unappreciated mechanism of PD-1–mediated suppression of T cell activity, which depends on the regulation of actin cytoskeleton dynamics in a signaling motif–independent manner. Description A mechanism by which the inhibitory receptor PD-1 suppresses T cell activation is revealed. Editor’s summary When engaged by its ligands, the receptor PD-1 inhibits the activation of T cells stimulated through the T cell receptor. Alleviating this effect is the basis of checkpoint inhibitors that promote antitumor immunity (see the Focus by Acharya and Kumari). Paillon et al. used imaging techniques to show that PD-1 signaling inhibited the formation of an immunological synapse between T cells and their target cells by preventing remodeling of the actin cytoskeleton in a manner independent of its intracellular, tyrosine-based signaling motifs. These findings suggest an alternative mechanism by which PD-1 regulates immune responses. —John F. Foley
The epigenetics effects of transposable elements are context dependent and not restricted to gene silencing

Transposable elements (TEs) represent a threat to genome integrity due to their proliferation capacity. Eukaryotic cells silence TEs through different epigenetic mechanisms, including the deposition of repressive histone marks. Previous studies have shown that repressive marks can spread to neighboring sequences. However, evidence for this spreading affecting nearby gene expression remains limited. Similarly, whether TEs induce changes in the enrichment of active histone marks genome-wide, and its potential impact on gene expression have not been widely studied. In this work, we performed a comprehensive study of the epigenetic effects of 2,235 TEs and their potential effects on nearby gene expression on D. melanogaster head, gut and ovary. While most of the TEs (816) induce the enrichment of the H3K9me3 repressive mark, with stronger epigenetic effects in the ovary, a substantial number (345 TEs) induce the enrichment of the H3K27ac active mark, particularly in the gut. We found that 70% of the H3K9me3 enriched TEs induced gene down-regulation, and 50% of the H3K27ac enriched TEs induced gene up-regulation. These changes in expression affect specific regulatory networks in head and gut while in ovary, genes were not enriched for any biological functions. Furthermore, TE epigenetic effects on gene expression are genomic context dependent. Finally, we found that TEs also affect gene expression by disrupting regions enriched for histone marks. Overall, our results show that TEs do generate regulatory novelty through epigenetic changes, with these epigenetic effects not restricted to gene silencing and being context dependent. Significance statement Transposable elements (TEs) are repetitive DNA sequences found in nearly all studied organisms that have the capacity to move within the genome. To prevent their proliferation, eukaryotic cells target TEs with repressive histone marks, an epigenetic signal that blocks their expression. While these repressive marks can spread to neighboring genes, the evidence of how this impacts gene expression is limited. Similarly, whether TEs also influence the enrichment and depletion of active histone marks and their genome-wide impact is not understood. In this work, we studied the histone mark enrichment of 2,235 polymorphic TEs across three body parts of D. melanogaster. Our results provide evidence for the genome-wide role of TEs in the generation of regulatory novelty through epigenetic changes.
Exploring connectivity of resting-state EEG between BCI-literate and -illiterate groups

Although Motor Imagery-based Brain-Computer Interface (MI-BCI) holds significant potential, its practical application faces challenges attributable to the phenomenon known as BCI-illiteracy. BCI researchers have attempted to predict BCI-illiteracy to mitigate this issue. As connectivity’s significance in neuroscience has grown, BCI researchers have applied connectivity to predict BCI-illiteracy with resting-state data. However, connectivity metrics’ use and interpretation of the results can be challenging for several reasons. Firstly, there are various connectivity metrics, each with its own advantages and disadvantages based on their underlying hypotheses and perspectives. These pros and cons are shaped by several factors, increasing the complexity of their application and interpretation. Secondly, it is unclear whether they are as acceptable as their developers have claimed. Thirdly, it is not evident which factor may influence the estimation of connectivity and which metric is suitable for this research. Therefore, this study conducted an empirical test to provide BCI researchers with a better understanding of connectivity. We analyzed three large public datasets using three functional connectivity (FC) and three effective connectivity (EC) metrics. Additionally, the structural difference in the resting-state network between BCI-literate and illiterate groups was examined. Our analysis revealed that the appropriate frequency range to measure connectivity varies depending upon the metric used. The alpha range was found to be suitable for FC, while the alpha, alpha + theta, and beta ranges were found to be appropriate for EC. Further, the results of estimating connectivity varied depending upon the dataset and metric used. Although we observed that BCI-literacy had stronger connections between nodes, no other significant structural differences were found between the two groups. However, BCI-literacy’s resting-state network displayed higher network efficiency compared to BCI-illiteracy, regardless of the metrics and dataset used. Therefore, it seems reasonable to use resting-state connectivity to predict BCI-illiteracy. Our conclusion is that each metric has its own specific hypothesis and perspective to measure connectivity under certain conditions.
Making predictions using poorly identified mathematical models

Many commonly used mathematical models in the field of mathematical biology involve challenges of parameter non-identifiability. Practical non-identifiability, where the quality and quantity of data does not provide sufficiently precise parameter estimates is often encountered, even with relatively simple models. In particular, the situation where some parameters are identifiable and others are not is often encountered. In this work we apply a recent likelihood-based workflow, called Profile-Wise Analysis (PWA), to non-identifiable models for the first time. The PWA workflow addresses identifiability, parameter estimation, and prediction in a unified framework that is simple to implement and interpret. Previous implementations of the workflow have dealt with idealised identifiable problems only. In this study we illustrate how the PWA workflow can be applied to both structurally non-identifiable and practically non-identifiable models in the context of simple population growth models. Dealing with simple mathematical models allows us to present the PWA workflow in a didactic, self–contained document that can be studied together with relatively straightforward Julia code provided on GitHub. Working with simple mathematical models allows the PWA workflow prediction intervals to be compared with gold standard full likelihood prediction intervals. Together, our examples illustrate how the PWA workflow provides us with a systematic way of dealing with non-identifiability, especially compared to other approaches, such as seeking ad hoc parameter combinations, or simply setting parameter values to some arbitrary default value. Importantly, we show that the PWA workflow provides insight into the commonly–encountered situation where some parameters are identifiable and others are not, allowing us to explore how uncertainty in some parameters, and combinations of some parameters, regardless of their identifiability status, influences model predictions in a way that is insightful and interpretable.
Crosstalk between Gut Sensory Ghrelin Signaling and Adipose Tissue Sympathetic Outflow Regulates Metabolic Homeostasis

The stomach-derived orexigenic hormone ghrelin is a key regulator of energy homeostasis and metabolism in humans. The ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR), is widely expressed in the brain and gastrointestinal vagal sensory neurons, and neuronal GHSR knockout results in a profoundly beneficial metabolic profile and protects against diet-induced obesity (DIO) and insulin resistance. Here we show that in addition to the well characterized vagal GHSR, GHSR is robustly expressed in gastrointestinal sensory neurons emanating from spinal dorsal root ganglia. Remarkably, sensory neuron GHSR deletion attenuates DIO through increased energy expenditure and sympathetic outflow to adipose tissue independent of food intake. In addition, neuronal viral tract tracing reveals prominent crosstalk between gut non-vagal sensory afferents and adipose sympathetic outflow. Hence, these findings demonstrate a novel gut sensory ghrelin signaling pathway critical for maintaining energy homeostasis.
hictk: blazing fast toolkit to work with .hic and .cool files

Motivation Hi-C is gaining prominence as a method for mapping genome organization. With declining sequencing costs and a growing demand for higher-resolution data, efficient tools for processing Hi-C datasets at different resolutions are crucial. Over the past decade, the . hic and Cooler file formats have become the de-facto standard to store interaction matrices produced by Hi-C experiments in binary format. Interoperability issues make it unnecessarily difficult to convert between the two formats and to develop applications that can process each format natively. Results We developed hictk, a toolkit that can transparently operate on . hic and . cool files with excellent performance. The toolkit is written in C++ and consists of a C++ library with Python and R bindings as well as CLI tools to perform common operations directly from the shell, including converting between . hic and . mcool formats. We benchmark the performance of hictk and compare it with other popular tools and libraries. We conclude that hictk significantly outperforms existing tools while providing the flexibility of natively working with both file formats without code duplication. Availability The hictk library, Python bindings and CLI tools are released under the MIT license as a multi-platform application available at github.com/paulsengroup/hictk. Pre-built binaries for Linux and macOS are available on bioconda. Python bindings for hictk are available on GitHub at github.com/paulsengroup/hictkpy, while R bindings are available on GitHub at github.com/paulsengroup/hictkR. Contact jonas.paulsen@ibv.uio. no Supplementary information Supplementary data are available at Bioinformatics online.
Aging impairs skeletal muscle regeneration by promoting fibro/fatty degeneration and inhibiting inflammation resolution via fibro-adipogenic progenitors

Skeletal muscle regeneration depends on the function of fibro/adipogenic progenitors (FAPs). Here we show that aging impairs myogenic stem cells by disrupting the integration of extracellular matrix and immunomodulatory functions within the stem cell niche, thereby promoting fibro/fatty degeneration. We identify the FAP-secreted protein Periostin as a niche factor that is decreased in aged muscle and in circulation of aged humans with low-exercise lifestyle. Periostin controls FAP-expansion after injury and its depletion fate-regulates FAPs towards adipogenesis. This leads to delayed pro- to anti-inflammatory macrophage transition during regeneration. Transplantation of young FAPs with high Periostin secretion, but not Periostin-deficient FAPs, into aged muscle restores inflammation resolution and successful regeneration. Mechanistically, Periostin activates Focal adhesion kinase- and AKT-signaling in macrophages via integrins to promote an anti-inflammatory profile, which synchronizes matrix-derived mechanosensory signaling and immunomodulation. These results uncover a novel role of FAP-based regulation that orchestrates successful muscle regeneration and prevents fibro/fatty degeneration.
Experimental Deformation of Sedimentary Rocks Under Confining Pressure: Pore Pressure Tests

Berea sandstone, Marianna limestone, Hasmark dolomite, Repetto siltstone, and Muddy shale have been subjected to triaxial compression tests in which the external confining pressures and internal pore pressures (to 2 kilobars) are applied and measured independently. The interstitial water pressure is maintained constant throughout the test, and porosity changes are determined as functions of permanent shortening. The ultimate strength and ductility of porous rocks are found to depend on effective confining pressure--the difference between external and internal pressures when the pore fluid is chemically inert, the permeability is sufficient to insure pervasion and uniform pressure distribution, and the configuration of pore space is such that the interstitial hydrostatic (neutral) pressure is transmitted fully throughout the solid framework. At high effective pressures (about 1 kilobar) porosity decreases with progressive permanent strain. At intermediate pressures (about 500 bars) the porosity remains essentially constant for compressions as great as 20 per cent, and at low pressures (about 200 bars and less) the rocks are dilatant. Microscopic examination of the sandstone reveals that grain breakage becomes progressively less important as pore pressure is increased until the deformation becomes entirely intergranular. Since the aggregate is initially closely packed, the shortening leads inevitably to increased void volume. An explanation of the pore pressure effects on the basis of Coulomb friction is consistent with the empirical data. High pore pressure reduces internal friction (but does not modify the coefficient). The rock is weak and relatively brittle; faulting is favored. These facts support the Hubbert-Rubey theory of large-scale overthrust faulting and enhance our understanding of diapir structures in shales, of sandstone dikes, of localized faulting in zones of "abnormal" formation pressures, and of high interstitial pressures in young intensely folded rocks of low permeability.
Empirical Relationship between Moment Magnitude and Nuttli Magnitude for Small-magnitude Earthquakes in Southeastern Canada

The most common catalog magnitude for eastern North America is the Nuttli magnitude (Nuttli, 1973), referred to as MN or MbLg . The Nuttli magnitude is based on the amplitude of the Lg phase (multiply reflected and refracted shear waves). MN is quickly and easily determined from the time series, making it convenient for routine catalog purposes. The moment magnitude scale (Hanks and Kanamori, 1979) is generally preferred by seismologists for many applications, as it is more reflective of the actual size of the earthquake. Moment magnitude ( M ), however, is more difficult to routinely determine reliably, especially for small to moderate earthquakes. Thus it is useful to develop empirical relationships between M and MN , so that M can be estimated for events for which only MN has been determined. Atkinson (1993) developed the empirical relationship \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[\ M{\ }={\ }0.98{\ }M_{N}-0.39\] \end{document}(1) for eastern North American earthquakes within the magnitude range of 4 < MN < 6. In this note, we extend this relationship below MN 4, using well recorded small earthquakes in the Charlevoix seismic zone (CSZ) of southeastern Canada, where the relatively dense Charlevoix array of the Canadian National Seismographic Network (CNSN) has been active since 1994. Seven seismographic stations comprise the Charlevoix array, separated by no more than 40 km, as shown in Figure 1; events of magnitude as small as MN 1.0 are usually well recorded (Lamontagne, 1999). We combine the calculated moment magnitudes from …
Extending Merlin-Arthur Classifiers for Improved Interpretability

In my doctoral research, I aim to address the interpretability challenges associated with deep learning by extending the Merlin-Arthur Classifier framework. This novel approach employs a pair of feature selectors, including an adversarial player, to generate informative saliency maps. My research focuses on enhancing the classifier’s performance and exploring its applicability to complex datasets, including a recently established human benchmark for detecting pathologies in X-ray images. Tackling the min-max optimization challenge inherent in the Merlin-Arthur Classifier for high-dimensional data, I will explore and apply diverse stabilization strategies to bolster the framework’s robustness and training stability. Finally, the goal is to expand the framework beyond pixel-level saliency maps to encompass modalities, such as text and learned feature spaces, fostering a comprehensive understanding of interpretability across various domains and data types.
On Min-Max Graph Balancing with Strict Negative Correlation Constraints

We consider the min-max graph balancing problem with strict negative correlation (SNC) constraints. The graph balancing problem arises as an equivalent formulation of the classic unrelated machine scheduling problem, where we are given a hypergraph G = ( V, E ) with vertex-dependent edge weight function p : E × V 7→ Z ≥ 0 that represents the processing time of the edges (jobs). The SNC constraints, which are given as edge subsets C 1 , C 2 , . , C k , require that the edges in the same subset cannot be assigned to the same vertex at the same time. Under these constraints, the goal is to compute an edge orientation (assignment) that minimizes the maximum workload of the vertices. In this paper, we conduct a general study on the approximability of this problem. First, we show that, in the presence of SNC constraints, the case with max e ∈ E | e | = max i | C i | = 2 is the only case for which approximation solutions can be obtained. Further generalization on either direction, e.g., max e ∈ E | e | or max i | C i | , will directly make computing a feasible solution an NP-complete problem to solve. Then, we present a 2-approximation algorithm for the case with max e ∈ E | e | = max i | C i | = 2, based on a set of structural simplifications and a tailored assignment LP for this problem. We note that our approach is general and can be applied to similar settings, e
Trustworthy Enough? Evaluation of an AI Decision Support System for Healthcare Professionals

Exploring end-users’ needs and involving them in designing and evaluating an AI system should be a priority. Understanding the system is essential to assess whether to trust it or not. This paper discusses a use case of a decision support system integrated into a platform for healthcare professionals (medical call operators and nurses). The system navigates them by predicting what intervention should be taken when an accident happens to a patient at home. Our use case demonstrates the importance of human-centred evaluation methods and potential struggles with mixed methods as detected by differences between qualitative and quantitative approaches. A subjective scale in combination with group interviews was used to evaluate the trust towards the system. The results showed that while users expressed a relatively high trust in the scale, the qualitative insights indicated uncertainty and the need for better explainability to trust the decision support system. In line with the results, we point out the need for better human-centred evaluation methods, as the current subjective scale needs to be complemented by qualitative methods to ensure rich insights.
Sea Level Change in the Western James Bay Region of Subarctic Ontario: Emergent Land and Implications for Treaty No. 9

In 1905 and 1906, the Cree of the southwestern James Bay region signed Treaty No. 9 whereby they relinquished to the Canadian government their claim to the lands south of the Albany River (the northern boundary of the province of Ontario at the time). The official text of Treaty No. 9 made no mention of land submerged below water cover, and thus the Cree did not relinquish such regions at that time. By contrast, the Cree of the northwestern James Bay and southwestern Hudson Bay region who signed the 1929–30 Adhesions to Treaty No. 9 relinquished their claims to “land covered by water” for the area bounded on the south by the northerly limit of Treaty No. 9, as this clause was specifically included in the text of the adhesion. The issue of “land covered by water” is significant because the western James Bay region has been, and will continue to be, subject to sea level changes associated with ongoing adjustments due to the last ice age and modern global warming signals. In the absence of detailed maps, we used models of these processes, constrained by available geophysical and geodetic data sets, to retrodict shoreline changes and the rate of land emergence over the last two centuries within the boundaries specified by Treaty No. 9. We also project shoreline migration to the end of the 21st century within the same region. The rate of land emergence since 1905 in the area south of the Albany River is estimated as ~3.0 km 2 /yr. Over the next century, land will continue to emerge in this region at a mean rate of ~1.4 km 2 /yr. This emergent land should be a subject of consideration within any comprehensive land claim put forward by the Cree; in this regard, it will be interesting to see how the Canadian judicial system and the Comprehensive Claims Branch handle the novel issue of emergent land.
Connected Vertex Cover on AT-Free Graphs

Asteroidal Triple (AT) in a graph is an independent set of three vertices such that every pair of them has a path between them avoiding the neighbourhood of the third. A graph is called AT-free if it does not contain any asteroidal triple. A connected vertex cover of a graph is a subset of its vertices which contains at least one endpoint of each edge and induces a connected subgraph. Settling the complexity of computing a minimum connected vertex cover in an AT-free graph was mentioned as an open problem in Escoffier et al. [6]. In this paper we answer the question by presenting an exact polynomial time algorithm for computing a minimum connected vertex cover problem on AT-free graphs.