Miracle-dz/UniFAR-FTUs huggingface dataset:
Leptospiral lipopolysaccharide dampens inflammation through upregulation of autophagy adaptor p62 and NRF2 signaling in macrophages

Leptospira interrogans are pathogenic bacteria responsible for leptospirosis, a worldwide zoonosis. All vertebrates can be infected, and some species like humans are susceptible to the disease whereas rodents such as mice are resistant and become asymptomatic renal carriers. Leptospires are stealth bacteria that are known to escape several immune recognition pathways and resist killing mechanisms. We recently published that leptospires may survive intracellularly and exit macrophages, in part by escaping xenophagy, a pathogen-targeting form of autophagy. Interestingly, autophagy is one of the antimicrobial mechanisms often highjacked by bacteria to evade the host immune response. In this study we therefore explored whether leptospires subvert the key molecular players of autophagy to facilitate the infection. We showed in macrophages that leptospires triggered a specific accumulation of autophagy-adaptor p62 in puncta-like structures, without major alteration of autophagy flux. Unlike active bacterial mechanisms described to date, we demonstrated that leptospires trigger p62 accumulation using a passive mechanism of LPS signaling via TLR4/TLR2. p62 is a central pleiotropic protein, not only involved in autophagy, but also mediating cell stress and death, via the translocation of transcription factors. We demonstrated that Leptospira-driven accumulation of p62 induced the translocation of transcription factor NRF2. However, NRF2 translocation upon Leptospira infection did not result as expected in antioxydant response, but dampened the production of inflammatory mediators such as iNOS/NO, TNF and IL6. Overall, these findings highlight a novel passive bacterial mechanism linked to p62/NRF2 signaling that decreases inflammation and contributes to the stealthiness of leptospires.
Genome-wide peptidoglycan profiling of Vibrio cholerae

Most bacteria cells are protected by a peptidoglycan cell wall. Defining the chemical structure of the peptidoglycan has been instrumental to characterize cell wall associated proteins and to illuminate the mode of action of cell wall-acting antibiotics. However, a major roadblock for a comprehensive understanding of peptidoglycan homeostasis has been the lack of methods to conduct large-scale, systematic studies. Here we have developed and applied an innovative high throughput peptidoglycan analytical pipeline to analyze the entire non-essential, arrayed mutant library of Vibrio cholerae. The unprecedented breadth of these analyses revealed that peptidoglycan homeostasis is preserved by a large percentage of the genome organized in complex networks that functionally link peptidoglycan features with genetic determinants. As an example, we discovered a novel bifunctional penicillin-binding protein in V. cholerae. Collectively, genome-wide peptidoglycan profiling provides a fast, easy, and unbiased method for systematic identification of the genetic determinants of peptidoglycan synthesis and remodeling.
Spitzer/Infrared Array Camera near-infrared features in the outer parts of S4G galaxies

We present a catalogue and images of visually detected features, such as asymmetries, extensions, warps, shells, tidal tails, polar rings, and obvious signs of mergers or interactions, in the faint outer regions (at and outside of R_(25)) of nearby galaxies. This catalogue can be used in future quantitative studies that examine galaxy evolution due to internal and external factors. We are able to reliably detect outer region features down to a brightness level of 0.03 MJy sr^(−1) pixel^(−1) at 3.6 μm in the Spitzer Survey of Stellar Structure in Galaxies (S^4G). We also tabulate companion galaxies. We find asymmetries in the outer isophotes in 22 ± 1 per cent of the sample. The asymmetry fraction does not correlate with galaxy classification as an interacting galaxy or merger remnant, or with the presence of companions. We also compare the detected features to similar features in galaxies taken from cosmological zoom re-simulations. The simulated images have a higher fraction (33 per cent) of outer disc asymmetries, which may be due to selection effects and an uncertain star formation threshold in the models. The asymmetries may have either an internal (e.g. lopsidedness due to dark halo asymmetry) or external origin.
On the evolution of the plant phytochrome chromophore biosynthesis

Phytochromes are biliprotein photoreceptors present in plants, algae, certain bacteria and fungi. Land plant phytochromes use phytochromobilin (PΦB) as the bilin chromophore. Phytochromes of streptophyte algae, the clade within which land plants evolved, employ phycocyanobilin (PCB), leading to a more blue-shifted absorption spectrum. Both chromophores are synthesized by ferredoxin-dependent bilin reductases (FDBRs) starting from biliverdin IXα (BV). In cyanobacteria and chlorophyta, BV is reduced to PCB by the FDBR phycocyanobilin:ferredoxin oxidoreductase (PcyA), whereas, in land plants, BV is reduced to PФB by phytochromobilin synthase (HY2). However, phylogenetic studies suggested the absence of any ortholog of PcyA in streptophyte algae and the presence of only PФB biosynthesis related genes (HY2). The HY2 of the early diverging streptophyte alga Klebsormidium nitens (formerly Klebsormidium flaccidum) was already indirectly indicated to be involved in PCB biosynthesis. Here, we overexpressed and purified a His6-tagged variant of K. nitens HY2 (KflaHY2) in E. coli. Employing anaerobic bilin reductase activity assays and coupled phytochrome assembly assays, we were able to confirm the product and to identify intermediates of the reaction. Site-directed mutagenesis revealed two aspartate residues critical for catalysis. While it was not possible to convert KflaHY2 into a PΦB-producing enzyme by simply exchanging the catalytic pair, the biochemical investigation of two additional members of the HY2 lineage enabled us to define two distinct clades, the PCB-HY2 and the PΦB-HY2 clade. Overall, our study gives insight into the evolution of the HY2 lineage of FDBRs.
Effects of Aging on Cortical Representations of Continuous Speech

Understanding speech in a noisy environment is crucial in day-to-day interactions, and yet becomes more challenging with age, even for healthy aging. Age-related changes in the neural mechanisms that enable speech-in-noise listening have been investigated previously; however, the extent to which age affects the timing and fidelity of encoding of target and interfering speech streams are not well understood. Using magnetoencephalography (MEG), we investigated how continuous speech is represented in auditory cortex in the presence of interfering speech, in younger and older adults. Cortical representations were obtained from neural responses that time-locked to the speech envelopes using speech envelope reconstruction and temporal response functions (TRFs). TRFs showed three prominent peaks corresponding to auditory cortical processing stages: early (∼50 ms), middle (∼100 ms) and late (∼200 ms). Older adults showed exaggerated speech envelope representations compared to younger adults. Temporal analysis revealed both that the age-related exaggeration starts as early as ∼50 ms, and that older adults needed a substantially longer integration time window to achieve their better reconstruction of the speech envelope. As expected, with increased speech masking, envelope reconstruction for the attended talker decreased and all three TRF peaks were delayed, with aging contributing additionally to the reduction. Interestingly, for older adults the late peak was delayed, suggesting that this late peak may receive contributions from multiple sources. Together these results suggest that there are several mechanisms at play compensating for age-related temporal processing deficits at several stages, but which are not able to fully reestablish unimpaired speech perception. NEW & NOTEWORTHY We observed age-related changes in cortical temporal processing of continuous speech that may be related to older adults’ difficulty understanding speech in noise. These changes occur in both timing and strength of the speech representations at different cortical processing stages, and depend on both noise condition and selective attention. Critically, their dependency on noise condition changes dramatically among the early, middle, and late cortical processing stages, underscoring how aging differentially affects these stages.
KCNH2 encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression

KCNH2 encodes hERG1, the voltage-gated potassium channel that conducts the rapid delayed rectifier potassium current (IKr) in human cardiac tissue. hERG1 is one of the first channels expressed during early cardiac development, and its dysfunction is associated with intrauterine fetal death, sudden infant death syndrome, cardiac arrhythmia, and sudden cardiac death. Here, we identified a novel hERG1 polypeptide (hERG1NP) that is targeted to the nuclei of immature cardiac cells, including hiPSC-CMs and neonatal rat cardiomyocytes. The nuclear hERG1NP immunofluorescent signal is diminished in matured hiPSC-CMs and absent from adult rat cardiomyocytes. Antibodies targeting distinct hERG1 channel epitopes demonstrated that the hERG1NP signal maps to the hERG1 distal C-terminal domain. KCNH2 deletion using CRISPR simultaneously abolished IKr and the hERG1NP signal in hiPSC-CMs. We then identified a putative nuclear localization sequence (NLS) within the distal hERG1 C-terminus, 883-RQRKRKLSFR-892. Interestingly, the distal C-terminal domain was targeted almost exclusively to the nuclei when overexpressed HEK293 cells. Conversely, deleting the NLS from the distal peptide abolished nuclear targeting. Similarly, blocking α or β1 karyopherin activity diminished nuclear targeting. Finally, overexpressing the putative hERG1NP peptide in the nuclei of HEK cells significantly reduced hERG1a current density, compared to cells expressing the NLS-deficient hERG1NP or GFP. These data identify a developmentally regulated polypeptide encoded by KCNH2, hERG1NP, whose presence in the nucleus indirectly modulates hERG1 current magnitude and kinetics.
Diel activity patterns of vector mosquito species in the urban environment: Implications for vector control strategies

Florida and Texas continue to be afflicted by mosquito-borne disease outbreaks such as dengue and West Nile virus disease and were the most affected states by the Zika outbreak of 2016-2017. Mathematical models have been widely used to study the population dynamics of mosquitoes as well as to test and validate the effectiveness of arbovirus outbreak responses and mosquito control strategies. The objective of this study is to assess the diel activity of mosquitoes in Miami-Dade, Florida and Brownsville, Texas, and to evaluate the effectiveness of simulated adulticide treatments on local mosquito populations. To assess variations in the diel activity patterns, mosquitoes were collected hourly for 96 hours once a month from May through November 2019 in Miami-Dade and Brownsville, Texas. We then performed a PERMANOVA followed by the SIMPER method to assess which species contributed the most to the observed differences. Finally, we used a mathematical model to simulate the population dynamics of 5 mosquito vector species to evaluate the effectiveness of the simulated adulticide applications. A total of 14,502 mosquitoes comprising 17 species were collected in Brownsville and 10,948 mosquitoes comprising 19 species were collected in Miami-Dade. Aedes aegypti was the most common mosquito species collected every hour in both cities and peaking in abundance in the morning and the evening. Our modeling results indicate that the effectiveness of adulticide applications varied greatly depending on the hour of the treatment. Overall, 9 PM was the best time for adulticide applications targeting all mosquito vector species in Miami-Dade and Brownsville. Our results indicate that the timing of adulticide spraying interventions should be carefully considered by local authorities based on the ecology of mosquito species in the focus area.
Ab initio predictions for 3D structure and stability of single- and double-stranded DNAs in ion solutions

The three-dimensional (3D) structure and stability of DNA are essential to understand/control their biological functions and aid the development of novel materials. In this work, we present a coarse-grained (CG) model for DNA based on the RNA CG model proposed by us, to predict 3D structures and stability for both dsDNA and ssDNA from the sequence. Combined with a Monte Carlo simulated annealing algorithm and CG force fields involving the sequence-dependent base-pairing/stacking interactions and an implicit electrostatic potential, the present model successfully folds 20 dsDNAs (≤52nt) and 20 ssDNAs (≤74nt) into the corresponding native-like structures just from their sequences, with an overall mean RMSD of 3. 4Å from the experimental structures. For DNAs with various lengths and sequences, the present model can make reliable predictions on stability, e.g., for 27 dsDNAs with/without bulge/internal loops and 24 ssDNAs including pseudoknot, the mean deviation of predicted melting temperatures from the corresponding experimental data is only ~2.0℃. Furthermore, the model also quantificationally predicts the effects of monovalent or divalent ions on the structure stability of ssDNAs/dsDNAs. Author Summary To determine 3D structures and quantify stability of single- (ss) and double-stranded (ds) DNAs is essential to unveil the mechanisms of their functions and to further guide the production and development of novel materials. Although many DNA models have been proposed to reproduce the basic structural, mechanical, or thermodynamic properties of dsDNAs based on the secondary structure information or preset constraints, there are very few models can be used to investigate the ssDNA folding or dsDNA assembly from the sequence. Furthermore, due to the polyanionic nature of DNAs, metal ions (e.g., Na+ and Mg2+) in solutions can play an essential role in DNA folding and dynamics. Nevertheless, ab initio predictions for DNA folding in ion solutions are still an unresolved problem. In this work, we developed a novel coarse-grained model to predict 3D structures and thermodynamic stabilities for both ssDNAs and dsDNAs in monovalent/divalent ion solutions from their sequences. As compared with the extensive experimental data and available existing models, we showed that the present model can successfully fold simple DNAs into their native-like structures, and can also accurately reproduce the effects of sequence and monovalent/divalent ions on structure stability for ssDNAs including pseudoknot and dsDNAs with/without bulge/internal loops.
The aperiodic exponent of subthalamic field potentials reflects excitation/inhibition balance in Parkinsonism

Periodic features of neural time series data, such as local field potentials (LFP), are often quantified using power spectra. While the aperiodic exponent of spectra is typically disregarded, it is nevertheless modulated in a physiologically-relevant manner and was recently hypothesised to reflect excitation/inhibition (E/I) balance in neuronal populations. Here, we used a cross-species in vivo electrophysiological approach to test the E/I hypothesis in the context of experimental and idiopathic Parkinsonism. We demonstrate in dopamine-depleted rats that aperiodic exponents and power at 30-100 Hz in subthalamic nucleus (STN) LFPs reflect defined changes in basal ganglia network activity; higher aperiodic exponents tally with lower levels of STN neuron firing and a balance tipped towards inhibition. Using STN-LFPs recorded from awake Parkinson’s patients, we show that higher exponents accompany dopaminergic medication and deep brain stimulation (DBS) of STN, consistent with untreated Parkinson’s manifesting as reduced inhibition and hyperactivity of STN. These results suggest that the aperiodic exponent of STN-LFPs in Parkinsonism reflects E/I balance, and might be a candidate biomarker for adaptive DBS.
Zika virus-induces metabolic alterations in fetal neuronal progenitors that could influence in neurodevelopment during early pregnancy

Neuronal progenitor subtypes have distinct fate restrictions regulated by time-dependent activation of energetic pathways. Thus, the hijacking of cellular metabolism by Zika virus (ZIKV) to support its replication may contribute to damage in the developing fetal brain. Here, we showed that ZIKV replicates differently in two glycolytically distinct hiPSC-derived neuronal progenitors that correspond to early and late progenitors in the forebrain. This differential replication alters the transcription of metabolic genes and upregulates the glycolytic capacity of progenitor subtypes. Analysis using Imagestream® revealed that, during early stages of infection, ZIKV replication in early progenitors increases lipid droplet abundance and decreases mitochondrial size and membrane potential. During later stages infection, early progenitors show increased subcellular distribution of lipid droplets, whilst late progenitors show decreased mitochondria size. The finding that there are hi-NPC subtype-specific alterations of cellular metabolism during ZIKV infection may help to explain the differences in brain damage over each trimester.
Co-fluctuations of neural activity define intra-V1 networks related to perceptual organization

Using functional resonance imaging (fMRI), we studied the relationship between perceptual organization and network topology within the primary visual cortex (V1). Twenty-six humans (male and female) were recorded during active observation of two Global and Local Navon letters. Correlations between fMRI fluctuations from different V1 sites were measured (after removing stimulus-evoked signals) in windows specific to each condition. Intra-V1, like brain-wide networks, presented an overall decrease of correlations during stimulation compared to baseline but with increased statistical dimensionality. Massive edgewise testing and network based-statistics (both corrected by FDR) identified differences in connection strengths between stimuli that were mapped to the visual field. Global letters elicited long links mainly connecting V1 sites mapping the lower left/right visual quadrants. Shorter links were associated with local letters, primarily mapped within the lower-left visual quadrant. These connections were not observed in the time-locked (feedforward) responses shared across participants, and their lengths exceeded V1 population receptive field sizes. Thus, these networks reflect activity idiosyncratic to each participant, possibly generated by interactions within or feedback to V1. Perception would sculpt V1 connectivity, with specific increases in link strengths (in a background of decreases). These findings could help shed light on V1 as a “cognitive blackboard”.
Re-evaluating frontopolar and temporoparietal contributions to detection and discrimination confidence

Previously, we identified a subset of regions where the relation between decision confidence and univariate fMRI activity was quadratic, with stronger activation for both high and low compared to intermediate levels of confidence. We further showed that, in a subset of these regions, this quadratic modulation appeared only for confidence in detection decisions about the presence or absence of a stimulus, and not for confidence in discrimination decisions about stimulus identity (Mazor, Friston & Fleming, 2021). Here, in a pre-registered follow-up experiment, we sought to replicate our original findings and identify the origins of putative detection-specific confidence signals by introducing a novel asymmetric-discrimination condition: a discrimination task with the signal-detection properties of a detection task. This task required discriminating two alternatives (two different grating tilts) but was engineered such that the distribution of perceptual evidence was asymmetric, just as in yes/no detection. We successfully replicated the quadratic modulation of subjective confidence in prefrontal, parietal and temporal cortices. However, in contrast to our original report, this quadratic effect was similar in detection and discrimination responses, but stronger in the novel asymmetric-discrimination condition. We interpret our findings as weighing against the detection-specificity of confidence signatures and speculate about possible alternative origins of a quadratic modulation of decision confidence.
Beyond mean fitness: demographic stochasticity and resilience matter at tree species climatic edges

Aim Linking local population dynamics and species distributions is critical to predicting the impacts of climate change. While many studies focus on the mean fitness of populations, theory shows that species distributions can be shaped by demographic stochasticity or population resilience. Here we examine how mean fitness (measured by invasion rate), demographic stochasticity, and resilience (measured by the ability to recover from disturbance) constrain populations at the edges compared to the climatic center. Location Europe: Spain, France, Germany, Finland, and Sweden. Period Forest inventory data used for fitting the models cover the period from 1985 to 2013. Major taxa Dominant European tree species; Angiosperms and Gymnosperms. Methods We developed dynamic population models covering the entire life cycle of 25 European tree species with climatically dependent recruitment models fitted to forest inventory data. We then ran simulations using integral projection and individual-based models to test how invasion rates, risk of stochastic extinction, and ability to recover from stochastic disturbances differ between the center and edges of species’ climatic niches. Results Results varied among species, but in general, demographic constraints were stronger at warm edges and for species in harsher climates. Conversely, recovery was more limiting at cold edges. In addition, we found that for several species, constraints at the edges were due to demographic stochasticity and recovery capacity rather than mean fitness. Main conclusion Our results highlight that mean fitness is not the only mechanism at play at the edges; demographic stochasticity and population capacity to recover also matter for European tree species. To understand how climate change will drive species range shifts, future studies will need to analyse the interplay between population mean growth rate and stochastic demographic processes as well as disturbances.
Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor

Prolonged pausing of the transcription machinery may lead to the formation of three-stranded nucleic acid structures, called R-loops, typically resulting from the annealing of the nascent RNA with the template DNA. Unscheduled persistence of R-loops and RNA polymerases may interfere with transcription itself and other essential processes such as DNA replication and repair. Senataxin (SETX) is a putative helicase, mutated in two neurodegenerative disorders, which has been implicated in the control of R-loop accumulation and in transcription termination. However, understanding the precise role of SETX in these processes has been precluded by the absence of a direct characterisation of SETX biochemical activities. Here, we purify and characterise the helicase domain of SETX in parallel with its yeast orthologue, Sen1. Importantly, we show that SETX is a bona fide helicase with the ability to resolve R-loops. Furthermore, SETX has retained the transcription termination activity of Sen1 but functions in a species-specific manner. Finally, subsequent characterisation of two SETX variants harbouring disease-associated mutations shed light into the effect of such mutations on SETX folding and biochemical properties. Altogether, these results broaden our understanding of SETX function in gene expression and the maintenance of genome integrity and provide clues to elucidate the molecular basis of SETX-associated neurodegenerative diseases.