Miracle-dz/UniFAR-FTUs huggingface dataset:
Assessing uncertainty in connective field estimations from resting state fMRI activity

Connective Field (CF) modeling estimates the local spatial integration between signals in distinct cortical visual field areas. As we have shown previously using 7T data, CF can reveal the visuotopic organization of visual cortical areas even when applied to BOLD activity recorded in the absence of external stimulation. This indicates that CF modeling can be used to evaluate cortical processing in participants in which the visual input may be compromised. Furthermore, by using Bayesian CF modelling it is possible to estimate the co-variability of the parameter estimates and therefore, apply CF modeling to single cases. However, no previous studies evaluated the (Bayesian) CF model using 3T resting-state fMRI data, although this is important since 3T scanners are much more abundant and more often used in clinical research than 7T ones. In this study, we investigate whether it is possible to obtain meaningful CF estimates from 3T resting state (RS) fMRI data. To do so, we applied the standard and Bayesian CF modeling approaches on two RS scans interleaved by the acquisition of visual stimulation in 12 healthy participants. Our results show that both approaches reveal good agreement between RS- and visual field (VF)-based maps. Moreover, the 3T observations were similar to those previously reported at 7T. In addition, to quantify the uncertainty associated with each estimate in both RS and VF data, we applied our Bayesian CF framework to provide the underlying marginal distribution of the CF parameters. Finally, we show how an additional CF parameter, beta, can be used as a data-driven threshold on the RS data to further improve CF estimates. We conclude that Bayesian CF modeling can characterize local functional connectivity between visual cortical areas from RS data at 3T. In particular, we expect the ability to assess parameter uncertainty in individual participants will be important for future clinical studies. Highlights Local functional connectivity between visual cortical areas can be estimated from RS-fMRI data at 3T using both standard CF and Bayesian CF modelling. Bayesian CF modelling quantifies the model uncertainty associated with each CF parameter on RS and VF data, important in particular for future studies on clinical populations. 3T observations were qualitatively similar to those previously reported at 7T.
Effects of External Stimulation on Psychedelic State Neurodynamics

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes such as personality changes. These findings are particularly intriguing given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g. from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience, by studying participants under the effects of LSD or placebo, either with gross state changes (eyes closed vs. open) or different stimulus (no stimulus vs. music vs. video). Results show that while brain entropy increases with LSD in all the experimental conditions, it exhibits largest changes when subjects have their eyes closed. Furthermore, brain entropy changes are consistently associated with subjective ratings of the psychedelic experience, but this relationship is disrupted when participants are viewing video — potentially due to a “competition” between external stimuli and endogenous LSD-induced imagery. Taken together, our findings provide strong quantitative evidence for the role of context in modulating neural dynamics during a psychedelic experience, underlining the importance of performing psychedelic psychotherapy in a suitable environment. Additionally, our findings put into question simplistic interpretations of brain entropy as a direct neural correlate of conscious level. Significance Statement The effects of psychedelic substances on conscious experience can be substantially affected by contextual factors, which play a critical role in the outcomes of psychedelic therapy. This study shows how context can modulate not only psychological, but also neurophysiological phenomena during a psychedelic experience. Our findings reveal distinctive effects of having eyes closed after taking LSD, including a more pronounced change on the neural dynamics, and a closer correspondence between brain activity and subjective ratings. Furthermore, our results suggest a competition between external stimuli and internal psychedelic-induced imagery, which supports the practice of carrying out psychedelic therapy with patients having their eyes closed.
Kinetic model of small RNA-mediated regulation suggests that a small RNA can regulate co-transcriptionally

Small RNAs (sRNAs) are important regulators of gene expression in bacteria, particularly during stress responses. Many genetically and biochemically well characterized sRNAs regulate gene expression post-transcriptionally, by affecting translation and degradation of the target mRNA after they bind to their targets through base pairing. However, how regulation at each of these levels quantitatively contributes to the overall efficacy of sRNA-mediated regulation is not well understood. Here we present a general approach combining imaging and mathematical modeling to determine kinetic parameters at different levels of sRNA-mediated gene regulation. Unexpectedly, our data reveal that certain previously characterized sRNAs are able to regulate some targets co-transcriptionally, rather strictly post-transcriptionally, and suggest that sRNA-mediated regulation can occur early in the mRNA’s lifetime, perhaps as soon as the sRNA binding site is transcribed. In addition, our data suggest several important kinetic steps that may determine the efficiency and differential regulation of multiple mRNA targets by an sRNA. Particularly, binding of sRNA to the target mRNA is likely the rate-limiting step and may dictate the regulation hierarchy observed within an sRNA regulon.
Genetic diversity analysis of the D614G mutation in SARS-CoV-2

In this work, we evaluated the levels of genetic diversity in 18 genomes of SARS-CoV-2 carrying the D614G mutation, coming from Malaysia and Venezuela and publicly available at the National Center of Biotechnology and Information (NCBI). These haplotypes were previously used for phylogenetic analysis, following the LaBECom protocols. All gaps and unconserved sites were extracted for the construction of a phylogenetic tree. As specific methodologies for paired FST estimators, Molecular Variance (AMOVA), Genetic Distance, mismatch, demographic and spatial expansion analyses, molecular diversity and evolutionary divergence time analyses, 20,000 random permutations were always used. The results revealed the presence of only 57 sites of polymorphic and parsimonium-informative among the 29,827bp analyzed and the analyses based on FST values confirmed the presence of two distinct genetic entities with fixation index of 22% and with a higher component of population variation (78.14%). Tau variations revealed a significant time of divergence, supported by mismatch analysis of the observed distribution (τ = 42%). It is safe to say that the small number of existing polymorphisms should not reflect major changes in the protein products of viral populations in both countries and this consideration provides the safety that, although there are differences in the haplotypes studied, these differences are minimal for both regions analyzed geographically and, therefore, it seems safe to extrapolate the levels of polymorphism and molecular diversity found in the samples for other mutant genomes of SARS-CoV-2 in other countries. This reduces speculation about the possibility of large differences between mutant strains of SARS-CoV-2 (D614G) and wild strains, at least at the level of their protein products, although the mutant form has higher transmission speed and infection. The analyses suggest that possible variations in protein products, of the wild virus in relation to its mutant form, should be minimal, bringing peace of mind as to the increased risk of death from the new form of the virus, as well as possible problems of gradual adjustments in some molecular targets for vaccines.
Extensive MET alterations confer clinical response to MET inhibitors in gliomas

Activating alterations of the MET gene are well-characterized oncogenic drivers, and MET inhibitors could successfully treat several tumor types with MET alterations, including gliomas with PTPRZ1-MET fusion. However, the full diversity and prevalence of MET alterations in gliomas are still lacking to accurately identify a subset of patients likely to benefit from MET inhibitor treatment. Here, we interrogated genomic profiles of 1,351 gliomas, and further identify 60 cases harboring MET alterations, including MET fusions and various MET exon skipping events. MET RNA alterations, but not MET amplification, are highly enriched in the secondary glioblastomas (sGBM) with significantly worse prognosis. Further molecular analysis has shown that MET RNA alterations acting an additive effects of MET overexpression are induced in the course of glioma evolution. In vitro and clinical studies indicate cells and patients harboring MET alterations have better response to MET inhibitors. Collectively, these data suggest that a subgroup of gliomas harboring MET alterations likely to have benefit from MET-targeted therapy.
Identification of compounds enhancing Aqp4 stop codon readthrough

An unusual stop codon readthrough event generates a conserved C-terminally elongated variant of the water channel protein Aquaporin 4 (AQP4). In the brain, AQP4 is astrocyte-specific, required for normal functioning of the glymphatic system, and involved in the clearance of the Alzheimer’s associated protein Amyloid beta. Further, the readthrough variant is localized exclusively perivascularly, and the perivascular pool of AQP4 is reduced in Alzheimer’s and several other neurological diseases. However, there are currently no means of increasing or restoring the perivascular pool AQP4. Here we identify a compound that can enhance Aqp4 stop codon readthrough. We screened 2600 compounds, mostly approved drugs and pharmacologically active natural compounds, using a luciferase reporter system. 28 candidate lead compounds were then subjected to a variety of secondary screening steps using orthogonal reporter systems and characterizing dose-response activities. Finally, we tested the top compounds’ abilities to generate readthrough of the endogenous Aqp4 transcript, identifying Apigenin as an enhancer of this biological phenomenon. This compound can allow modulation of readthrough in experimental systems, mechanistic studies of programmed readthrough, and suggests the potential for modulating Alzheimer’s disease through pharmacological enhancement of perivascular AQP4.
Testing alternative phylogenetic hypotheses for the tent tortoise species complex (Reptilia, Testudinidae) using multiple data types and methods

We examined genetic differentiation in the highly polymorphic and taxonomically confusing tent tortoise (Psammobates tentorius) species complex in southern Africa, using three types of molecular markers (nDNA, mtDNA and microsatellite DNA) and morphological data. The Approximate Bayesian Computation based simulation analyses advocated an alternative phylogenetic hypothesis for the tent tortoise species complex, which was better and more inclusive in explaining its genealogical history. Based on the evidence derived from the sequence, microsatellite and morphology data, a four species scheme (among the seven mtDNA clades) appears to be the best taxonomic solution for the systematic puzzle of the P. tentorius species complex, namely, “C1+C4+C5+C7”, “C3”, “C2” and “C6”. The microsatellite datasets yielded similar genetic structure and gene flow patterns among the seven mtDNA clades in comparison to the sequence DNA. Evidence was found of possible hybridization between C1 and C2 in their intergradation zone, but not between C2 and C4. Results of the inbreeding analyses provided strong evidence of inbreeding in the eastern population of C1 and southern population of C2, which may be indicative of a bottleneck effect.
Prednisolone rescues Duchenne Muscular Dystrophy phenotypes in human pluripotent stem cells-derived skeletal muscle in vitro

Duchenne Muscular Dystrophy (DMD) is a devastating genetic disease leading to degeneration of skeletal muscles and premature death. How dystrophin absence leads to muscle wasting remains unclear. Here, we describe an optimized protocol to differentiate human induced Pluripotent Stem Cells (iPSC) to a late myogenic stage. This allows to recapitulate classical DMD phenotypes (mislocalization of proteins of the Dystrophin-glycoprotein associated complex (DGC), increased fusion, myofiber branching, force contraction defects and calcium hyperactivation) in isogenic DMD-mutant iPSC lines in vitro. Treatment of the myogenic cultures with prednisolone (the standard of care for DMD) can dramatically rescue force contraction, fusion and branching defects in DMD iPSC lines. This argues that prednisolone acts directly on myofibers, challenging the largely prevalent view that its beneficial effects are due to anti-inflammatory properties. Our work introduces a new human in vitro model to study the onset of DMD pathology and test novel therapeutic approaches.
Enhancer of Zeste Homolog 2 (Ezh2) is essential for patterning of multiple musculoskeletal tissues but dispensable for tendon differentiation

An efficient musculoskeletal system depends on the precise assembly and coordinated growth and function of muscles, skeleton and tendons. However, the mechanisms that drive integrated musculoskeletal development and coordinated growth and differentiation of each of these tissues are still being uncovered. Epigenetic modifiers have emerged as critical regulators of cell fate differentiation, but so far almost nothing is known about their roles in tendon biology. Previous studies have shown that epigenetic modifications driven by Enhancer of zeste homolog 2 (EZH2), a major histone methyltransferase, have significant roles in vertebrate development including skeletal patterning and bone formation. We now find that targeting Ezh2 through the limb mesenchyme also has significant effects on tendon and muscle patterning, likely reflecting the essential roles of early mesenchymal cues mediated by Ezh2 for coordinated patterning and development of all tissues of the musculoskeletal system. Conversely, loss of Ezh2 in the tendon cells did not disrupt the tendon cell fate suggesting that tenocyte differentiation and tendon maturation are independent of Ezh2 signaling.
How many and which species to plant? A multi-trait-based approach to select species to restore ecosystem services

It has been increasingly argued that ecological restoration should focus more on targeting ecosystem services than on species composition of reference ecosystems. In this sense, the role that species play on community assembly and functioning through their functional traits is very relevant, because effect traits mediate ecosystem processes, ultimately resulting in provision of ecosystem services. One major challenge in ecological restoration is to know which species to use that will deliver the target ecosystem services. We developed an algorithm to select the minimum set of species that maximize the functional richness (FRic) and the functional redundancy (FR) of the restored community, a proxy for the provision of multiple ecosystem services and the resilience of the system to environmental changes, respectively. For this, we simulated the restoration of 24 riparian woody communities of the Brazilian Cerrado. Using the species pool of each original local community, we ran restoration simulations for gradually increasing species richness until reaching the total species richness of the original local community. We computed FRic and FR for each simulated restoration community using the traits specific leaf area, maximum plant height and seed mass. Our simulation results indicate that multiple ecosystem services could be restored with an average of 66% of the species of the original community. Moreover, an average of 59% of the species would be needed to restore communities resilient to environmental changes. Our approach contributes to solving one of the major challenges of ecological restoration, which is defining how many and which species should be used to achieve functional targets. We believe this approach can help in projects of restoration by enabling restoration practitioners to select minimum alternative sets of species that optimize the provision of multiple ecosystem services in a resilient restored ecosystem.
Ivermectin reduces coronavirus infection in vivo: a mouse experimental model

SARS-CoV2 is a single strand RNA virus member of the type 2 coronavirus family, responsible for causing COVID-19 disease in humans. The objective of this study was to test the ivermectin drug in a murine model of coronavirus infection using a type 2 family RNA coronavirus similar to SARS-CoV2, the mouse hepatitis virus (MHV). BALB/cJ female mice were infected with 6,000 PFU of MHV-A59 (Group Infected; n=20) and immediately treated with one single dose of 500 μg/kg of ivermectin (Group Infected + IVM; n=20), or were not infected and treated with PBS (Control group; n=16). Five days after infection/treatment, mice were euthanized to obtain different tissues to check general health status and infection levels. Overall results demonstrated that viral infection induces the typical MHV disease in infected animals, with livers showing severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while ivermectin administration showed a better health status with lower viral load (23,192 AU; p<0.05) and few livers with histopathological damage (p<0.05), not showing statistical differences with control mice (P=NS). Furthermore, serum transaminase levels (aspartate aminotransferase and alanine aminotransferase) were significantly lower in treated mice compared to infected animals. In conclusion, ivermectin seems to be effective to diminish MHV viral load and disease in mice, being a useful model for further understanding new therapies against coronavirus diseases.
Adenomatous Polyposis Coli Loss Controls Cell Cycle Regulators and Response to Paclitaxel

Adenomatous Polyposis Coli (APC) is lost in approximately 70% of sporadic breast cancers, with an inclination towards triple negative breast cancer (TNBC). TNBC is treated with traditional chemotherapy, such as paclitaxel (PTX); however, tumors often develop drug resistance. We previously created APC knockdown cells (APC shRNA1) using the human TNBC cells, MDA-MB-157, and showed that APC loss induces PTX resistance. To understand the mechanisms behind APC-mediated PTX response, we performed cell cycle analysis and analyzed cell cycle related proteins. Cell cycle analysis indicated increased G2/M population in PTX-treated APC shRNA1 cells compared to PTX-treated controls, suggesting that APC expression does not alter PTX-induced G2/M arrest. We further studied the subcellular localization of the G2/M transition proteins, cyclin B1 and CDK1. The APC shRNA1 cells had increased CDK1, which was preferentially localized to the cytoplasm, and increased CDK6. RNA-sequencing was performed to gain a global understanding of changes downstream of APC loss and identified a broad mis-regulation of cell cycle-related genes in APC shRNA1 cells. Our studies are the first to show an interaction between APC and taxane response in breast cancer. The implications include designing combination therapy to re-sensitize APC-mutant breast cancers to taxanes using the specific cell cycle alterations.
Unraveling the world of halophilic and halotolerant bacteria in cheese by combining cultural, genomic and metagenomic approaches

Halophilic and halotolerant bacteria are generally assumed to live in natural environments, although they may also be found in foods such as cheese and seafood. These salt-loving bacteria have only been occasionally characterized in cheese, and studies on their ecological and technological functions are still scarce. We therefore selected 13 traditional cheeses in order to systematically characterize these microorganisms in their rinds via cultural, genomic and metagenomic methods. Using different salt-based media, we identified 35 strains with unique 16S rRNA and rpoB gene sequences, whose whole genome was sequenced. The most frequently isolated species are the halotolerant Gram-positive bacteria Brevibacterium aurantiacum (6) and Staphylococcus equorum (3), which are also frequently added as starters. Their genomic analyses confirm the high genetic diversity of B. aurantiacum and reveal the presence of two subspecies in S. equorum, as well as the genetic proximity of several cheese strains to bovine isolates. Additionally, we isolated 15 Gram-negative strains, potentially defining ten new species of halophilic cheese bacteria, in particular for the genera Halomonas and Psychrobacter. The use of these genomes as a reference to complement those existing in the databases allowed us to study the representativeness of 66 species of halophilic and halotolerant bacteria in 74 cheese rind metagenomes. The Gram-negative species are particularly abundant in a wide variety of cheeses with high moisture, such as washed-rind cheeses. Finally, analyses of co-occurrences reveal assemblies, including the frequent coexistence of several species of the same genus, forming moderately complex ecosystems with functional redundancies that probably ensure stable cheese development. IMPORTANCE Salt is commonly added to food to avoid the growth of pathogens by lowering water activity, resulting in profound changes in the medium that lead to the development of particular ecosystems dominated by halophilic and halotolerant bacteria, communities that probably originate in the natural environment. In order to explore these communities that have been poorly studied in food up until now, we developed a combined approach that includes cultures, genomics and metagenomics to deconstruct these ecosystems in cheese rinds. This approach allowed us to isolate 26 different species, ten of which belong to still undescribed species that could be used as references to promote advances in functional studies of this particular world. The metagenomic scan of 74 cheese rind samples for the assembly of 66 halophilic and halotolerant species showed that these bacteria are widely distributed and form moderately complex ecosystems where related species coexist and probably jointly contribute to safe and efficient cheese development.