Miracle-dz/UniFAR-FTUs huggingface dataset:
Contingency Management Concept Generation for U-Space System

Contingency management in aviation is a vital concept that ensures safety, security, and efficiency in operations. To fully benefit from the envisioned Advanced Air Mobility system, the need of a structured and system-wide contingency planning will be even more important since the air transportation system paradigm will shift into a highly automated system that includes high-density traffic. The complexity will increase considerably by enlarging the operations to the underserved urban areas. Therefore, the new system needs to provide a more agile, accessible, and flexible environment. In this paper, the need of a contingency management from a holistic approach is described and the base requirements to build such a system are defined by considering the roles and responsibilities of each stakeholder that are defined for the U-space system. Alongside the defined requirements, the tasks of the stakeholders and the expected main contingency sources are explained to have a better understanding of the system. The objective of this work is to provide the base guidelines that help to set appropriate actions by relevant stakeholder under an adverse condition which might compromise the safety and security of the operations within the air traffic network.
Rapid macropinocytic transfer of α-synuclein to lysosomes

The nervous system spread of alpha-synuclein fibrils is thought to cause Parkinson’s disease (PD) and other synucleinopathies, yet the mechanisms underlying internalization and cellular spread are enigmatic. Here we use confocal and super-resolution microscopy, subcellular fractionation and electron microscopy (EM) of immunogold labelled alpha-synuclein preformed fibrils (PFF) to demonstrate that this fibril form of alpha-synuclein undergoes rapid internalization and is targeted directly to lysosomes in as little as 2 minutes. Uptake of PFF is disrupted by macropinocytic inhibitors and circumvents classical endosomal pathways. Immunogold-labelled PFF are seen at the highly curved inward edge of membrane ruffles, in newly formed macropinosomes, in multivesicular bodies and in lysosomes. While most fibrils remain in lysosomes, a portion is transferred to neighboring naïve cells along with markers of exosomes. These data indicate that PFF use a unique internalization mechanism as a component of cell-to-cell propagation.
Functional brain-wide network mapping during acute stress exposure in rats: Interaction between the lateral habenula and cortical, amygdalar, hypothalamic and monoaminergic regions

Upon stress exposure a broad network of structures comes into play in order to provide adequate responses and restore homeostasis. It has been known for decades that the main structures engaged during the stress response are the medial prefrontal cortex, the amygdala, the hippocampus, the hypothalamus, the monoaminergic systems (noradrenaline, dopamine, serotonin), and the periaqueductal gray. The lateral habenula (LHb) is an epithalamic structure directly connected to prefrontal cortical areas and to the amygdala, whereas it functionally interacts with the hippocampus. Also, it is a main modulator of monoaminergic systems. The LHb is activated upon exposure to basically all types of stressors, suggesting it is also involved in the stress response. However, it remains unknown if and how the LHb functionally interacts with the broad stress response network. In the current study we performed in rats a restraint stress procedure followed by immunohistochemical staining of the c-Fos protein throughout the brain. Using Graph Theory-based functional connectivity analyses, we confirm the principal hubs of the stress network (e.g. prefrontal cortex, amygdala, periventricular hypothalamus), and show that the LHb is engaged during stress exposure in close interaction with the medial prefrontal cortex, the lateral septum, and the medial habenula. In addition, we performed DREADD-induced LHb inactivation during the same restraint paradigm in order to explore its consequences on the stress response network. This last experiment gave contrasting results as the DREADD ligand alone, clozapine-N-oxide, was able to modify the network. GRAPHICAL ABSTRACT GRAPHICAL ABSTRACT TEXT In this study, using immunohistochemical staining of the immediate early gene c-fos and graph theory-based functional correlational analyses, we aimed at unravelling the possible engagement of the lateral habenula (LHb) within the stress response network during acute stress exposure (10-min restraint) in rats. We found that the medial part of the LHb (LHbM) was preferentially engaged, and that this engagement was concomitant to this of structures such as the medial prefrontal cortex (mPFC), the insular cortex (Ins), hypothalamic (PVH) and thalamic (PVT) paraventricular nuclei, the extended amygdala, comprising the Bed nucleus of the stria terminalis (BNST) and the entire amygdala (AMG), as well as the dopaminergic ventral tegmental area (VTA) and the serotonergic dorsal raphe nucleus (RD). This suggests upon stressful situations the LHbM serves as a relay of cortical, thalamic, hypothalamic and temporal information, further transmitted to midbrain monoaminergic systems to probably initiate coping strategies.
Three ALS genes regulate expression of the MHC class II antigen presentation pathway

Here we report that the major histocompatibility complex II (MHC II) antigen presentation pathway is regulated by the ALS-causative genes, FUS, TAF15, or MATR3. Of >6000 proteins detected by quantitative mass spectrometry, the subunits of the MHC II heterodimer, HLA-DR, were the top 2 downregulated proteins in HeLa knock outs (KO) of these ALS genes, but not the related gene, EWSR1. Moreover, CD74, which is the 3rd essential component of HLA-DR, was downregulated in the 3 KOs. We show that the downregulations are due to loss of CIITA, a transcription factor dedicated to expression of MHC II genes. Thus, our results reveal the 1st shared cellular pathway regulated by multiple ALS genes, and this pathway is ALS genes -> CIITA -> MHC II genes. We obtained the same results in HMC3 cells, a microglia cell line, showing that loss of the MHC II pathway extends to an ALS-relevant cell type in the central nervous system (CNS). Furthermore, the MHC II pathway is downregulated in hematopoietic progenitor cells (HPCs) bearing the ALS FUSR495X mutation. This observation may be highly significant to ALS pathogenesis as HPCs give rise to a multitude of CNS-specific and systemic immune cells, both of which have known or suspected roles in ALS. Together, our data raise the possibility that loss of the MHC II pathway in a large range of immune cells results in global failure of the immune system to protect motor neurons from damage that leads to the disease. Consequently, CIITA and the other genes in the MHC II pathway may be important new therapeutic targets for the disease.
Neglecting normalization impact in semi-synthetic RNA-seq data simulation generates artificial false positives

By reproducing differential expression analysis simulation results presented by Li et al, we identified a caveat in the data generation process. Data not truly generated under the null hypothesis led to incorrect comparisons of benchmark methods. We provide corrected simulation results that demonstrate the good performance of dearseq and argue against the superiority of the Wilcoxon rank-sum test as suggested by Li et al. Please see related Research article with DOI 10.1186/s13059-022-02648-4.
Distinct cortical networks subserve spatio-temporal sampling in vision through different oscillatory rhythms

Although visual input arrives continuously, sensory information is segmented into discrete events. Here, the neural correlates of spatiotemporal binding in male/female human subjects were investigated with MEG using two tasks where separate flashes were presented on each trial but were perceived, in a bi-stable way, as either a single, or two separate, events. The first task (two-flash fusion: TFF) involved judging one versus two flashes while in the second task (apparent motion: AM) participants judged coherent motion versus two stationary flashes. Results indicate two different functional networks underlying two unique aspects of visual temporal binding. In the TFF task, involving an integration window of ≈50 ms, evoked responses differed as a function of perceptual interpretation by ≈25 ms after stimuli presentation. Multivariate decoding of subjective perception based on prestimulus oscillatory phase was significant for alpha-band activity in the right medial temporal (MT) area, with the strength of pre-stimulus connectivity between early visual areas and MT being predictive of performance. In contrast, the longer integration window (≈130 ms) for AM showed evoked field differences only ≈250 ms after stimuli onset. Phase decoding of the perceptual outcome in the AM task was strongest for theta-band activity, localized to a right intra-parietal sulcus (IPS) source. Pre-stimulus connectivity between MT and IPS seeds in the theta band best predicted perceptual outcome. Overall, these results show a strong relationship between specific spatiotemporal binding windows and specific oscillations, linked to the information flow between different areas of the “where” and “when” visual processing pathways. Significance Statement Multiple neural rhythms seem relevant for sampling visual information across space and time, but the cortical networks underlying these fundamental computational principles of the visual system remain unexplored. We filled this gap by employing source-level multivariate decoding and connectivity analyses of magnetoencephalographic data recorded during an integration/segregation task of temporal and spatio-temporal events. We identified a first and faster network involving early visual areas (V2 to MT/V5) that determines the basic temporal resolution of visual perception at the speed of the alpha rhythm, and a second slower network involving parietal regions (IPS) that had a key role in the integration of more complex spatiotemporal events at a theta speed. These findings elucidate the neural mechanisms that transfer sensory information into temporal sequences.
Mutual repression between JNK/AP-1 and JAK/STAT stratifies cell behaviors during tissue regeneration

Epithelial repair relies on the activation of stress signaling pathways to coordinate cellular repair behaviors. Their deregulation is implicated in chronic wound and cancer pathologies. Despite such translational importance, an understanding of how spatial patterns of signaling pathways and repair behaviors arise in damaged tissues remains elusive. Using TNF-α/Eiger-mediated inflammatory damage to Drosophila imaginal discs, we uncover that JNK/AP-1 signaling cells act as paracrine organizers and initiate a mutual repression network that spatially segregates JNK/AP-1 and JAK/STAT signaling cells into distinct populations. While JNK/AP-1 signaling cells produce JAK/STAT-activating Upd ligands, these signal-sending cells suppress activation of JAK/STAT via Ptp61F. Conversely, responding cells with activated JAK/STAT suppress JNK activation via Zfh2. The resulting bistable segregation of signaling domains is associated with distinct cellular tasks and regenerative potential. While JNK/AP-1 signaling cells at the wound center act as paracrine organizers, their cell cycle is senescently arrested. Thus, compensatory proliferation occurs exclusively in JAK/STAT signaling cells at the wound periphery. This spatial stratification is essential for proper tissue repair, as co-activation of JNK/AP-1 and JAK/STAT in the same cells creates conflicting inputs on cell cycle progression, leading to excess apoptosis of senescently arrested organizer cells. Finally, we demonstrate that bistable spatial segregation of JNK/AP-1 and JAK/STAT drives senescent and proliferative behaviors in transient as well as chronic tissue damage models, and importantly, in RasV12, scrib tumors under the influence of JNK/AP-1 activity. Revealing this previously uncharacterized regulatory network between JNK/AP-1, JAK/STAT and associated cell behaviors have important implications for our conceptual understanding of tissue repair, chronic wound pathologies and tumor microenvironments, where both pathways are strongly implicated.
Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development.
Comparative genomics reveals insight into the evolutionary origin of massively scrambled genomes

Ciliates are microbial eukaryotes that undergo extensive programmed genome rearrangement that converts long germline chromosomes into smaller gene-rich somatic chromosomes. Three well-studied ciliates include Oxytricha trifallax, Tetrahymena thermophila and Paramecium tetraurelia, but only the Oxytricha lineage has a massively scrambled genome whose assembly requires hundreds of thousands of precise DNA joining events. Here we study the emergence of genome complexity by examining the origin and evolution of discontinuous and scrambled genes in the Oxytricha lineage. We sequenced, assembled and annotated the germline and somatic genomes of Euplotes woodruffi and the germline genome of Tetmemena sp. , and compared their genome rearrangement features to that of the model ciliate Oxytricha trifallax. The germline genome of Tetmemena is as massively scrambled and interrupted as Oxytricha’s: 13.6% of its gene loci rearrange via translocations and/or inversions. This study revealed that the earlier-diverged spirotrich, E. woodruffi, also has a scrambled genome, but approximately half as many loci (7.3%) are scrambled, supporting its position as a possible evolutionary intermediate in this lineage, in the process of accumulating complex genome rearrangements. Scrambled loci are more often associated with local duplications, supporting a simple model for the origin of scrambled genes via DNA duplication and decay.
Near-infrared diffuse in vivo flow cytometry

Significance Diffuse in vivo Flow Cytometry (DiFC) is an emerging technique for enumerating rare fluorescently labeled circulating cells non-invasively in the bloodstream. Thus far we have reported red and blue-green versions of DiFC. Use of near-infrared (NIR) fluorescent light would in principle allow use of DiFC in deeper tissues and would be compatible with emerging NIR fluorescence molecular contrast agents. Aim In this work, we describe the design of a NIR-DiFC instrument and demonstrate its use in optical flow phantoms in vitro and in mice in vivo. Approach We developed an improved optical fiber probe design for efficient collection of fluorescence from individual circulating cells, and efficient rejection of instrument autofluorescence. We built a NIR-DiFC instrument. We tested this with NIR fluorescent microspheres and cell lines labeled with OTL38 fluorescence contrast agent in a flow phantom model. We also tested NIR-DiFC in nude mice injected intravenously with OTL38-labeled L1210A cells. Results NIR-DiFC allowed detection of CTCs in flow phantoms with mean signal to noise ratios (SNRs) of 19 to 32 dB. In mice, fluorescently-labeled CTCs were detectable with mean SNR of 26 dB. NIR-DiFC also exhibited orders significantly lower autofluorescence and false-alarm rates than blue-green DiFC. Conclusions NIR-DiFC allows use of emerging NIR contrast agents. This work could pave the way for future use of NIR-DiFC in humans.
SpatialDEG: Identification of differentially expressed genes by leveraging spatial information in spatially resolved transcriptomic studies

Motivation Spatially resolved transcriptomics (SRT) technologies have been developed to simultaneously profile gene expression while retaining physical information. To explore differentially expressed genes using SRT in the context of various conditions, statistical methods are needed to perform spatial differential expression analysis. Results We propose that a new probabilistic framework, spatialDEG, can perform differential expression analysis by leveraging spatial information on gene expression with spatial information. SpatialDEG utilizes the average information algorithm and can be scalable to tens of thousands of genes. Comprehensive simulations demonstrated that spatialDEG can identify genes differentially expressed in tissues across different conditions with a controlled type-I error rate. We further applied spatialDEG to analyze datasets for human dorsolateral prefrontal cortex and mouse whole liver. Availability The R package spatialDEG can be downloaded from https://github.com/Shufeyangyi2015310117/spatialDEG.
Peptide Avidity for TCR on CD4 Effectors Determines the Extent of Memory Generation

The impact of initial peptide antigen affinity for TCR in driving memory fate has been studied previously, however its contributions when effectors contract to memory is unclear. To become memory, effector CD4 T cells must recognize antigen at 5-8 days post-infection, at what we call the “effector checkpoint. ” We examined whether peptide affinity for the TCR of effectors impacts the extent of memory and degree of protection against rechallenge. We made an influenza A virus (IAV) nucleoprotein (NP)-specific TCR transgenic strain, FluNP, and generated NP-peptide variants that bind FluNP TCR with a broad range of avidity. To vary avidity in vivo, we primed naïve donor FluNP in IAV-infected hosts, purified 6d FluNP effectors and co-transferred them with peptide-pulsed APC into uninfected second hosts. Higher affinity peptides yielded higher numbers of FluNP memory cells in the spleen and most dramatically in the lung and dLN, and drove better protection against lethal influenza infection. The major impact of avidity was on memory cell number, not cytokine production, and was already apparent within several days of transfer. We previously showed that autocrine IL-2 production during the effector checkpoint prevented default effector apoptosis and supported memory formation. Here, peptide avidity determined the level of IL-2 produced by effectors. IL-2Rα expression by APC drove more memory cell formation, suggesting that transpresentation of IL-2 by APC at this checkpoint enhanced CD4 memory generation. Secondary memory generation was also avidity-dependent. We propose this pathway selects CD4 effectors of highest affinity to progress to memory.
Mechanosensitive pore opening of a prokaryotic voltage-gated sodium channel

Voltage-gated ion channels orchestrate electrical activities that drive mechanical functions in contractile tissues such as the heart and gut. In turn, contractions change membrane tension and impact ion channels. Voltage-gated ion channels are mechanosensitive, but the mechanisms of mechanosensitivity remain poorly understood. Here, we leverage the relative simplicity of NaChBac, a prokaryotic sodium channel from Bacillus halodurans, to investigate its mechanosensitivity. In whole-cell experiments on heterologously transfected HEK293 cells, shear stress reversibly altered the kinetic properties of NaChBac and increased its maximum current, comparably to the mechanosensitive eukaryotic sodium channel NaV1.5. In single-channel experiments, patch suction reversibly increased the open probability of a NaChBac mutant with inactivation removed. A simple kinetic mechanism featuring a mechanosensitive pore opening transition explained the overall response to force, whereas an alternative model with mechanosensitive voltage sensor activation diverged from the data. Structural analysis of NaChBac identified a large displacement of the hinged intracellular gate, and mutagenesis at the hinge abolished NaChBac mechanosensitivity, further supporting the proposed mechanism. Overall, our results suggest that NaChBac responds to force because its pore is intrinsically mechanosensitive. This mechanism may apply to other voltage-gated ion channels, including NaV1.5.
Gammaherpesvirus ncRNAs share conserved features of binding and virulence despite lack of sequence conservation

Gammaherpesvirus (γHV) non-coding RNAs (ncRNAs) are integral modulators of viral infection. The γHVs engage RNA polymerase III (pol III)-dependent transcription of both host and viral ncRNAs, which contribute to viral establishment, gene expression, and pathogenesis. Viral ncRNAs, such as the EBV-encoded RNAs (EBERs), reportedly interact with multiple host RNA-binding proteins (RBPs) and contribute to inflammatory responses implicated in the development of malignancies. Here, we examined RBP interactions of the pol III-transcribed tRNA-miRNA encoded non-coding RNAs (TMERs) of murine γHV68, and the potential contributions of these and the related EBERs to in vivo pathogenesis. Using sequential enzymatic treatments, we found that several TMER1 forms retain a 5’-triphosphate, lending the possibility of recognition by the innate immune sensor RIG-I. We further examined the interactions of TMERs and EBERs with host RBPs, and found that multiple TMERs and EBERs interact with the La protein, though minimal interaction was detected with RIG-I during primary virus infection. Finally, we investigated the contributions of the TMERs and EBERs to disease in an immune-compromised mouse model with a series of viral recombinants. We found that expression of multiple single TMERs, or the EBERs expressed in place of the TMERs, was capable of restoring virulence to a viral recombinant lacking expression of all TMERs. Ultimately, these studies demonstrate that divergent pol III-transcribed γHV ncRNAs share interaction characteristics with two host RBPs and conserved contributions to disease, despite little to no significant sequence conservation. These findings support a model of convergent functions of the sequence-variable pol III-transcribed γHV ncRNAs. IMPORTANCE Viruses manipulate the infected cell and host inflammatory responses through expression of coding and non-coding RNAs. The gammaherpesviruses are a subfamily of herpesviruses associated with chronic inflammatory diseases and malignancies, especially in immune-compromised individuals. Among these, the human Epstein-Barr virus and murine gammaherpesvirus 68 (γHV68) express highly abundant, RNA polymerase III-dependent, short non-coding RNAs. Whether these sequence-divergent ncRNAs have conserved functional properties is unknown. By using viral recombinants to allow direct comparison of these ncRNAs during primary infection, we find that the sequence-divergent ncRNAs of γHV68 and EBV share a conserved property to bind to the host RNA binding protein, La, and function interchangeably to facilitate in vivo pathogenesis. These studies demonstrate that abundant, RNA polymerase III-dependent viral ncRNAs can potently function to alter the host cell landscape and promote disease in a sequence-independent manner.