Miracle-dz/UniFAR-FTUs huggingface dataset:
MyD88-TLR4-dependent choroid plexus activation precedes perilesional inflammation and edema in intracerebral hemorrhage

The functional neurological outcome of patients with intracerebral hemorrhage (ICH) strongly relates to the degree of secondary brain injury (ICH-SBI) evolving within days after the initial bleeding. Different mechanisms including the incitement of inflammatory pathways, dysfunction of the blood–brain barrier (BBB), activation of resident microglia, and an influx of blood-borne immune cells, have been hypothesized to contribute to ICH-SBI. Yet, the spatiotemporal interplay of specific inflammatory processes within different brain compartments has not been sufficiently characterized, limiting potential therapeutic interventions to prevent and treat ICH-SBI. Using a whole-blood injection model in mice, we systematically characterized the spatial and temporal dynamics of inflammatory processes after ICH using 7-Tesla magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional BBB assessment, and immunofluorescence average-intensity-mapping. We identified a pronounced early response of the choroid plexus (CP) peaking at 12 to 24h, that was characterized by inflammatory cytokine expression, epithelial and endothelial expression of leukocyte adhesion molecules, and the accumulation of leukocytes. In contrast, we observed a delayed secondary reaction pattern at the injection site (striatum) peaking at 96h, defined by gene expression corresponding to perilesional leukocyte infiltration and correlating to the delayed signal alteration seen on MRI. Pathway analysis revealed a dependence of the early inflammatory reaction in the CP on toll-like receptor 4 (TLR4) signaling via myeloid differentiation factor 88 (MyD88). TLR4 and MyD88 knockout mice corroborated this observation, lacking the early upregulation of adhesion molecules and leukocyte infiltration within the CP 24h after whole-blood injection. In conclusion, we report a biphasic brain reaction pattern after ICH with a MyD88-TLR4-dependent early inflammatory response of the CP, preceding inflammation, edema and leukocyte infiltration at the lesion site. Pharmacological targeting of the early CP-activation might harbor the potential to modulate the development of ICH-SBI. Graphical abstract Akeret, Buzzi et al. characterized the spatiotemporal dynamics after striatal whole blood injection in mice using magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional blood-brain barrier (BBB) assessment, and immunofluorescence average intensity mapping (IF). They report a biphasic brain reaction pattern with an early MyD88-TLR4-dependent inflammatory response of the CP, which preceded secondary inflammation and leukocyte infiltration at the perilesional site.
Genome-wide metabolite quantitative trait loci analysis (mQTL) in red blood cells from volunteer blood donors

The Red Blood Cell (RBC)-Omics study, part of the larger NHLBI-funded Recipient Epidemiology and Donor Evaluation Study (REDS-III), aims to understand the genetic contribution to blood donor RBC characteristics. Previous work identified donor demographic, behavioral, genetic and metabolic underpinnings to blood donation, storage, and - to a lesser extent - transfusion outcomes, but none have yet linked the genetic and metabolic bodies of work. We performed a Genome-Wide Association (GWA) analysis using RBC-Omics study participants with generated untargeted metabolomics data to identify metabolite quantitative trait loci (mQTL) in RBCs. We performed GWA analyses of 382 metabolites in 243 individuals imputed using the 1000 Genomes Project phase 3 all-ancestry reference panel. Analyses were conducted using ProbABEL and adjusted for sex, age, donation center, number of whole blood donations in the past two years, and first ten principal components of ancestry. Our results identified 423 independent genetic loci associated with 132 metabolites (p < 5×10−8). Potentially novel locus-metabolite associations were identified for FLVCR1 and choline, and for LPCAT3 and the lysophosphatidylserine 16.0, 18.0, 18.1, and 18.2; these associations are supported by published rare disease and mouse studies. We also confirmed previous metabolite GWA results for associations including N(6)-Methyl-L-lysine and PYROXD2, and various carnitines and SLC22A16. Association between pyruvate levels and G6PD polymorphisms was validated in an independent cohort and novel murine models of G6PD deficiency (African and Mediterranean variants). We demonstrate that it is possible to perform metabolomics-scale GWA analyses with a modest, trans-ancestry sample size. Key points Metabolite heterogeneity in fresh (<14 day old) RBCs donated by volunteer donors is linked to genetic polymorphisms; We report 2,831 high-confidence SNP-metabolite linkages (p < 5.0 × 10−8). Pyruvate levels in fresh RBCs are associated with glucose-6-phosphate dehydrogenase (G6PD) status
4.1N and SAP97 regulate different phases of AMPA receptor intracellular transport

Changes in the number of synaptic AMPA subtypes of glutamate receptors (AMPAR) underlie many forms of synaptic plasticity. These variations are controlled by a complex interplay between their intracellular transport (IT), export to the plasma membrane, stabilization at synaptic sites, and recycling. The differential molecular mechanisms involved in these various trafficking pathways and their regulation remains partly unknown. We have recently reported the visualization of AMPAR IT in cultured hippocampal neurons and demonstrated its regulation during synaptic plasticity inducing protocols (Hangen, Cordelieres et al., 2018), opening the path to the differential analysis of the mechanisms controlling AMPAR transport and exocytosis. The cytosolic C-terminal (C-ter.) domain of AMPAR GluA1 subunit is specifically associated with cytoplasmic proteins that could be implicated in the regulation of their IT such as 4.1N and SAP97. Here we analyze how interactions between GluA1 and 4.1N or SAP97 regulate IT and exocytosis at the plasma membrane in basal condition and after cLTP induction. We use sh-RNA against 4.1N and SAP97 and specific mutations and deletions of GluA1 C-ter. domain to characterize how these interactions are involved in coupling AMPAR to the transport machinery. The down-regulation of both 4.1N or SAP97 by shRNAs decrease GluA1 containing vesicle number, modify their transport properties and decrease GluA1 export to the PM, indicating their role in GluA1 IT. The total deletion of the C-ter. domain of GluA1 fully suppresses its IT. Disruption of GluA1 binding to 4.1N decreases the number of GluA1 containing transport vesicles, inhibits GluA1 externalization but does not affect the transport properties of the remaining GluA1 containing vesicles. This indicates a role of the 4.1N-GluA1 interaction during exocytosis of the receptor in basal transmission. In contrast, disrupting the binding between SAP97 and GluA1 modifies the basal transport properties of GluA1 containing vesicles and decreases GluA1 export to the plasma membrane. Importantly, disrupting GluA1 interaction with either 4.1N or SAP97 prevents both the cLTP induced increase in the number of GluA1 containing vesicles observed in control and GluA1 externalization. Our results demonstrate that specific interactions between 4.1N or SAP97 with GluA1 have different roles in GluA1 IT and exocytosis. During basal transmission, the binding of 4.1N to GluA1 allows the fusion/fission membrane exocytosis whereas the interaction with SAP97 is essential for GluA1 IT. During cLTP the interaction of 4.1N with GluA1 allows both IT and exocytosis of the receptor in hippocampal cultured neurons. Altogether, our results identify the differential roles of 4.1N and SAP97 in the control of various phases of GluA1 IT.
Rapid Evolution of Glycan Recognition Receptors Reveals an Axis of Host-Microbe Conflicts at Carbohydrate-Protein Interfaces

Detection of microbial pathogens is a primary function of many mammalian immune proteins. This can be accomplished through the recognition of diverse microbial-produced macromolecules including proteins, nucleic acids and carbohydrates. Many pathogens subvert host defenses by rapidly changing these structures to avoid detection, placing strong selective pressures on host immune proteins that repeatedly adapt to remain effective. Signatures of rapid evolution have been identified in numerous host immunity proteins involved in the detection of pathogenic protein substrates, but whether the same signals can be observed in host proteins engaged in interactions with other pathogen-derived molecules has received much less attention. This focus on protein-protein interfaces has largely obscured the study of fungi as contributors to host-pathogen evolutionary conflicts, despite their importance as a formidable class of vertebrate pathogens. Here, we provide evidence that many mammalian immune receptors involved in the detection of microbial glycans have been subject to recurrent positive selection. Notably, we find that rapidly evolving sites in these genes primarily cluster in key functional domains involved in carbohydrate recognition. Further, we identified convergent patterns of substitution in distinct primate populations at a site in the Melanin Lectin gene that has been associated with increased risk of invasive fungal disease. Our results also highlight the power of evolutionary analyses to reveal uncharacterized interfaces of host-pathogen conflict by identifying genes, such as CLEC12A, with strong signals of positive selection across multiple mammalian lineages. These results suggest that the realm of interfaces shaped by host-microbe conflicts extends beyond the world of host-viral protein-protein interactions and into the world of microbial glycans and fungi.
Slow and not so furious: de novo stomatal pattern formation during plant embryogenesis

The fates of cells on the leaf surface depend on positional cues and environmental signals. New stomata are formed away from existing ones to prevent disadvantageous clustering, but how are the initial precursors positioned? Mature embryos do not have stomata, but we provide transcriptomic, imaging, and genetic evidence that Arabidopsis embryos engage known stomatal fate and patterning factors to create regularly spaced stomatal precursor cells. Analysis of embryos from 35 plant species indicates this trait is conserved across angiosperm clades. Embryonic stomatal patterning in Arabidopsis is established in three stages: first broad SPEECHLESS (SPCH) expression, then coalescence of SPCH and its targets into discrete domains, and finally one round of symmetric division to create stomatal precursors. Lineage progression is then halted until after germination. We show that embryonic stomatal pattern enables quick stomatal differentiation and photosynthetic activity upon germination but also guides the formation of additional stomata as the leaf expands. In addition, key stomatal regulators are prevented from driving the fate transitions they can induce after germination, revealing stage-specific layers of regulation that control lineage progression during embryogenesis.
Decoy effect in shoaling decision making in zebrafish (Danio rerio)

Several organisms, from slime molds to humans, are known to violate normative principles of economic rationality in decision making. In animals, the neural circuitry underlying behaviors that violate or conform to normative rationality is relatively poorly understood. We investigated whether zebrafish, a model organism with a strong suite of functional neuroimaging and genetic manipulation tools, showed a decoy effect with respect to the principle of the Independence of Irrelevant Alternatives (IIA). We examined IIA in social decision-making by measuring revealed preferences from spatial trajectories of freely swimming individual zebrafish in an arena where they could view and perform shoaling behavior near conspecific zebrafish in adjacent display tanks. IIA was tested in terms of the invariance of shoaling choices between binary and ternary sets of various display fish group sizes. We provide the first report of evidence for the decoy effect in male zebrafish, but not in females. This opens up a range of possibilities to study the neural basis of context-dependent decision making.
What does heritability of Alzheimer’s disease represent?

Introduction Both late-onset Alzheimer’s disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability. Methods We compute heritability in five large independent cohorts (N = 7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set. Results SNP-based heritability of late onset Alzheimer’s disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% [SD = 8%] on average when the APOE region is excluded and an additional 1% [SD = 3%] when genome-wide significant regions were removed. A microglia gene-set explains 69–84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts. Conclusion The heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes.
Structural rearrangements of a caspase-like protease TPR-CHAT govern virus-host discrimination during type III-E CRISPR-Caspase immunity

The RNA-targeting type III-E CRISPR-gRAMP effector forms a complex with a caspase-like protease TPR-CHAT, but the mechanistic details of their functional relationship remain unknown. Here, we report on cryo-EM structures of gRAMPcrRNA and gRAMPcrRNA-TPR-CHAT complexes, before and after either self or non-self RNA target binding, elucidating mechanisms underlying RNA-targeting and non-self RNA-induced protease activation. Noteworthy, the associated TPR-CHAT adopts a strikingly distinct conformation on self versus non-self RNA targets, with nucleotides at position −1 and −2 of crRNA serving as a sensor. Only binding of non-self RNA target activates TPR-CHAT protease, leading to the cleavage of Csx30 protein. Furthermore, given that TPR-CHAT structurally resembles eukaryotic separase, our results implicate an ancient mechanism for separase regulation. Our findings should not only facilitate the development of gRAMP-based RNA manipulation tools, but also lead to a mechanistic understanding of the virus-host discrimination process governed by a caspase-like protease during type III-E CRISPR-Caspase immunity.
Neural responses to movie naturalistic stimuli are related to listening demand in cochlear implant users

There is a weak relationship between clinical and self-reported speech perception outcomes in cochlear implant (CI) listeners. Such poor correspondence may be due to differences in clinical and “real-world” listening environments and stimuli. Speech sounds in the real world are often accompanied by visual cues, background environmental noise and is generally in the context of a connected conversation. The aims of this study were to determine if brain responses to naturalistic speech could index speech perception and listening demand in CI users. Accordingly, we recorded high density EEG while CI users listened/watched a naturalistic stimulus (i.e., the television show, “The Office”). We used continuous EEG to quantify “speech neural tracking” (i.e., TRFs, temporal response functions) to the television show audio track and additionally 8–12 Hz (alpha) brain rhythms commonly related to listening effort. Background noise at three different signal-to-noise ratios (SNRs), +5, +10, and +15 dB were presented to vary the difficulty of following the television show mimicking a natural noisy environment. The task included an additional condition of audio-only (no video). After each condition, participants subjectively rated listening demand and the degree of words and conversations they felt they could understand. Fifteen CI users reported progressively higher degrees of listening demand and less words and conversation with increasing background noise. Listening demand and conversation understanding in the audio-only condition was comparable to that of the highest noise condition (+5 dB). The addition of the background noise reduced the degree of speech neural tracking. Mixed effect modeling showed that listening demand and conversation understanding were correlated to cortical speech tracking such that high demand and low conversation understanding lower associated with lower amplitude TRFs. In the high noise condition, greater listening demand was negatively correlated to parietal alpha power such that higher demand was related to lower alpha power. No significant correlations were observed between TRF/alpha and clinical speech perception scores. These results are similar to previous findings showing little relationship between speech perception and quality of life in CI users. However, the physiological responses to complex natural speech may anticipate aspects of quality-of-life measures such as self-perceived listening demand.
A Genome-Scale Atlas Reveals Complex Interplay of Transcription and Translation in an Archaeon

While the transcriptional regulation landscape of archaea has been extensively investigated, we currently have limited knowledge about post-transcriptional regulation and its driving mechanisms in this domain of life. In this study, we collected and integrated omics data from multiple sources and technologies to infer post-transcriptionally regulated genes and the putative mechanisms modulating their expression at the protein level in Halobacterium salinarum NRC-1. ABSTRACT The scale of post-transcriptional regulation and the implications of its interplay with other forms of regulation in environmental acclimation are underexplored for organisms of the domain Archaea. Here, we have investigated the scale of post-transcriptional regulation in the extremely halophilic archaeon Halobacterium salinarum NRC-1 by integrating the transcriptome-wide locations of transcript processing sites (TPSs) and SmAP1 binding, the genome-wide locations of antisense RNAs (asRNAs), and the consequences of RNase_2099C knockout on the differential expression of all genes. This integrated analysis has discovered that 54% of all protein-coding genes in the genome of this haloarchaeon are likely targeted by multiple mechanisms for putative post-transcriptional processing and regulation, with about 20% of genes likely being regulated by combinatorial schemes involving SmAP1, asRNAs, and RNase_2099C. Comparative analysis of mRNA levels (transcriptome sequencing [RNA-Seq]) and protein levels (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry [SWATH-MS]) for 2,579 genes over four phases of batch culture growth in complex medium generated additional evidence for the conditional post-transcriptional regulation of 7% of all protein-coding genes. We demonstrate that post-transcriptional regulation may act to fine-tune specialized and rapid acclimation to stressful environments, e.g., as a switch to turn on gas vesicle biogenesis to promote vertical relocation under anoxic conditions and modulate the frequency of transposition by insertion sequence (IS) elements of the IS200/IS605, IS4, and ISH3 families. Findings from this study are provided as an atlas in a public Web resource (https://halodata.systemsbiology.net). IMPORTANCE While the transcriptional regulation landscape of archaea has been extensively investigated, we currently have limited knowledge about post-transcriptional regulation and its driving mechanisms in this domain of life. In this study, we collected and integrated omics data from multiple sources and technologies to infer post-transcriptionally regulated genes and the putative mechanisms modulating their expression at the protein level in Halobacterium salinarum NRC-1. The results suggest that post-transcriptional regulation may drive environmental acclimation by regulating hallmark biological processes. To foster discoveries by other research groups interested in the topic, we extended our integrated data to the public in the form of an interactive atlas (https://halodata.systemsbiology.net).
Farasha: A Provable Permutation-based Parallelizable PRF

The pseudorandom function Farfalle , proposed by Bertoni et al. at ToSC 2017, is a permutation based arbitrary length input and output PRF. At its core are the public permutations and feedback shift register based rolling functions. Being an elegant and parallelizable de-sign, it is surprising that the security of Farfalle has been only investigated against generic cryptanalysis techniques such as differential/linear and algebraic attacks and nothing concrete about its provable security is known. To fill this gap, in this work, we propose Farasha , a new permutation-based parallelizable PRF with provable security. Farasha can be seen as a simple and provable Farfalle -like construction where the rolling functions in the compression and expansion phases of Farfalle are replaced by a uniform almost xor universal (AXU) and a simple counter, respectively. We then prove that in the random permutation model, the compression phase of Farasha can be shown to be an uniform AXU function and the expansion phase can be mapped to an Even-Mansour block cipher. Consequently, combining these two properties, we show that Farasha achieves a security of min { keysize, permutation size/2 } . Finally, we provide concrete instantiations of Farasha with AXU functions providing different performance trade-offs. We believe our work will bring new insights in further understanding the provable security of Farfalle - like constructions.
Supplemental Materials: Geometric control of sliding friction

We perform sliding experiments with geometrically controlled surfaces to monitor the influence of macroscopic periodic roughness on the friction force. A triangular tooth pattern is used which is fabricated on the surface of three materials, see Table S1. Triangular prisms with a depth of 20 mm are fabricated over a length of 60 mm. The plastic surfaces are manufactured with digital fabrication techniques. A commercially available resin, named Clear, is 3D printed with the Form 3 (Formlabs). Based on stereolithography, the liquid resin is cured into hardened plastic by photopolymerization with a print-resolution (both axis and lateral) of 25 μm [1]. For the aluminium (6082-T6 aluminium alloy) and stainless steel (AISI 316) surfaces, wire electrical discharge machining is used; the patterning is fabricated by removing material with electrical discharges (sparks) from a 0.25 mm brass wire. This technique has a resolution of 5.0 μm for the fabrication of mm-size macroscopic surface roughness. However, the resolution of this technique is significantly less for the fabrication of high surface slopes in μm-size surface patterns. The microscopic surface topography — the microscopic surface roughness — of all materials is measured prior to sliding laser-scanning profilometry (Keyence VK-X1000) over an area of 208 by 208 μm with a lateral resolution of 138 nm/pixel and 20 nm resolution in the height direction. The calculated root-mean-square surface height variation S q is listed in Table S1.