Miracle-dz/UniFAR-FTUs huggingface dataset:
Prevention of Drug-Induced Lung Fibrosis via Inhibition of the MRTF/SRF Transcription Pathway

Drug-induced lung fibrosis is a debilitating disease, linked to high morbidity and mortality. A number of drugs can cause fibrosis, many of which are used to treat cancer, including chemotherapy agents and immune checkpoint inhibitors. The MRTF/SRF transcription pathway has been proposed as a potential therapeutic target, as it is critical for myofibroblast differentiation, a hallmark of fibrosis. In human lung fibroblasts, the MRTF/SRF pathway inhibitor, CCG-257081, effectively decreased mRNA levels of downstream genes: smooth muscle actin and connective tissue growth factor, with IC50s of 4 and 15 μM, respectively. The ability of CCG-257081 to prevent inflammation and fibrosis, measured via pulmonary collagen content and histopathology, was tested in a murine model of chemotherapy-induced lung fibrosis. Animals were given intraperitoneal bleomycin for four weeks, and concurrently dosed with CCG-257081 (0, 10, 30, and 100 mg/kg PO), a clinical anti-fibrotic (nintedanib), or clinical standard of care (prednisolone). Mice treated with 100 mg/kg CCG-257081 gained weight vs. vehicle-treated control mice, while those receiving nintedanib and prednisolone lost significant weight. Hydroxyproline content and histological findings in tissue of animals on 100 mg/kg CCG-257081 were not significantly different from naive tissue, indicating successful prevention. Measures of tissue fibrosis were comparable between CCG-257081 and nintedanib, but only the MRTF/SRF inhibitor decreased plasminogen activator inhibitor-1 (PAI-1), a marker linked to fibrosis, in bronchoalveolar lavage fluid. Prednisolone led to marked increases in lung fibrosis. This study demonstrates the potential use of MRTF/SRF inhibitors to prevent drug-induced lung fibrosis in a clinically relevant model of drug-induced disease.
Orientations of Mistaken Point fronds indicate morphology impacted ability to survive turbulence

The Ediacaran organisms of the Mistaken Point E surface have provided crucial insight into early animal communities, including how they reproduced, the importance of Ediacaran height and what the most important factors were to their community dynamics. Here, we use this iconic community to investigate how morphological variation between eight taxa affected their ability to withstand different flow conditions. For each of Beothukis, Bradgatia, Charniodiscus procerus, Charniodiscus spinosus, Plumeropriscum, Primocandelabrum and Fractofusus we measured the orientation and length of their stems (if present) and their fronds. We statistically tested each taxon’s stem and frond orientation distributions to see whether they displayed a uniform or multimodal distribution. Where multimodal distributions were identified, the stem/frond length of each cohort was tested to identify if there were differences in size between different orientation groups. We find that Bradgatia and Thectardis show a bimodal felling direction, and infer that they were felled by the turbulent head of the felling flow. In contrast, the frondose rangeomorphs including Beothukis, Plumeropriscum, Primocandelabrum, and the arboreomorphs were felled in a single direction, indicating that they were upright in the water column, and were likely felled by the laminar tail of the felling flow. These differences in directionality suggests that an elongate habit, and particularly possession of a stem, lent greater resilience to frondose taxa against turbulent flows, suggesting that such taxa would have had improved survivability in conditions with higher background turbulence than taxa like Bradgatia and Thectardis, which lacked a stem and which had a higher centre of mass, which may have fared better in quieter water conditions.
Radiotherapy induces specific miRNA expression profiles in glioblastoma exosomes

Background Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor during adulthood. One of the major treatments is the association of surgery and a combination of chemo and radiotherapies. Despite its immediate efficiency, it fails to prevent the cancer recurrence in the irradiated area due to radioresistance mechanisms. MicroRNAs (miRNAs or miR) are small non-coding, single strand RNA molecules encoding to various specific genes and able to regulate their expression and induce the tumor cell survival leading to radioresistance. Small extracellular vesicles (EVs), or exosomes released by tumor cells in tumor microenvironment and blood circulation are able to transport and diffuse miRNAs and affect the microenvironment by spreading the miRNAs, which drive radioresistance. Aims To identify the variations of miRNAs expression induced by irradiation in human glioblastoma U87-MG cells and their secreted exosomes collected in supernatants. To analyze the miRNAs variations in EVs-derived from the plasma of patients during radiotherapy, in order to identify a miRNA signature induced by radiotherapy in a liquid biopsy. Materiel and methods U87-MG cells were cultured on plates and exposed to irradiation. miRNAs analyzes were performed in cells and in EVs isolated from cell supernatants to determine miRNAs expressions both in cells and in secreted exosomes before and after irradiation. Plasma-derived EVs were collected from 4 glioblastoma patients before and after surgery and radiotherapy treatments. Conclusion The analysis of miRNAs expression profiles in both GBM cells and their derived EVs revealed that miR profile changes after irradiation. However, the number of similar miR between cells or EVs, following cell irradiation, was restricted to 3 miRs alone suggesting that the irradiation-induced changes in the miR profile in the cells and their EVs are not closely linked. In this context, the miR profile in EVs from patients plasma was investigated to establish a potential link with the miRNAs profile observed in EVs from irradiated cells and to assess its relationship with the response to radiotherapy. Three miRs (different from those identified in cells) were common between EVs derived from cells and patients derived-exosomes. These miRs detected in circulating EVs could provide a specific and reliable signature in response to ionizing radiation, which could be useful for monitoring the effectiveness of radiotherapy. Further experiments on a larger patients population with clinical data could also help to define whether this signature might have a prognostic value on the response to radiotherapy.
Off-target expression of Cre-dependent adeno-associated viruses in wild type C57BL/6J mice

Adeno-associated viruses (AAVs) are a commonly used tool in neuroscience to efficiently label, trace, and/or manipulate neuronal populations. Highly specific targeting can be achieved through recombinase-dependent AAVs in combination with transgenic rodent lines that express Cre-recombinase in specific cell types. Visualization of viral expression is typically achieved through fluorescent reporter proteins (e.g., GFP or mCherry) packaged within the AAV genome. Although non-amplified fluorescence is usually sufficient to observe viral expression, immunohistochemical amplification of the fluorescent reporter is routinely used to improve viral visualization. In the present study, Cre-dependent AAVs were injected into the hippocampus and cortex of wild-type C57BL/6J mice. While we observed weak but consistent non-amplified off-target DIO expression in C57BL/6J mice, antibody amplification of the GFP or mCherry reporter revealed extensive Cre-independent viral expression. Off-target expression of DIO constructs in wild-type C57BL/6J mice occurred independent of vendor, AAV serotype or promoter. We also evaluated whether Cre-independent expression had functional effects via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). The DREADD agonist C21 had no effect on contextual fear conditioning or cFos expression in DIO-hM3Dq-mCherry+ cells of C57BL/6J mice. Taken together, our results indicate that DIO constructs have considerable off-target expression in wild type subjects. Our findings are particularly important for the design of experiments featuring sensitive systems and/or quantitative measurements that could be negatively impacted by off-target expression. Significance Statement Adeno-associated viruses (AAV) are widely used in neuroscience because of their safety and ease of use. Combined with specific promoters, Cre/loxP, and stereotaxic injections, highly specific targeting of cells and circuits within the brain can be achieved. In the present study we injected Cre-dependent AAVs into wild-type C57BL/6J mice and found considerable Cre-independent viral expression of AAVs encoding mCherry, GFP, or hM3Dq following immunohistochemical amplification of the fluorescent reporter protein. Importantly, we observed no functional effects of the Cre-independent expression in the hippocampus, as C21 had no detectable effect on DIO-hM3Dq-mCherry infected neurons in C57BL/6J mice. Given the widespread use of DIO rAAVs by the neuroscience community, our data supports careful consideration when using DIO constructs in control animals.
Metabolite elucidation of 2-Fluoro-Deschloroketamine (2F-DCK) using molecular networking across three complementary in vitro and in vivo models.

This work first aims to investigate metabolites of 2-Fluoro-Deschloroketamine (2F-DCK), a new arylcyclohexylamine derivatives (a group of dissociative ketamine-based substances) using two in vitro experimental approaches, and to compare obtained results by means of molecular networking. Metabolites of 2F-DCK were investigated using both human liver microsomes (HLMs) and hepatic (HepaRG) cell line incubates using molecular networking approach: 2F-DCK pure substance was incubated with HLMs for up to 1h at two concentrations (100 and 500 μM) and with HepaRG cells for two time periods (8h and 24h) at one concentration (20 μM). In vitro obtained results were subsequently applied to a 2F-DCK-related fatality case. In vitro-produced metabolites were investigated using high-resolution accurate mass spectrometry using Orbitrap mass analyzer technology. Thirteen metabolites were in vitro produced and several metabolic pathways can be postulated. Seven additional metabolites were found in post-mortem samples (bile and urine) of the case, comprising three phase II metabolites, which appear to be minor in vivo metabolites. HLMs and HepaRG cell models appear to be complementary and obtained data allowed the identification of several specific 2F-DCK metabolites in biological samples. In practical terms, observed metabolic ratios suggested that nor-2F-DCK (208.1137 m/z) and a hydrogenated metabolite (224.1443 m/z) could be proposed as reliable metabolites to be recorded in HRMS libraries in order to improve detection of 2F-DCK use.
Couple Religiosity and Well-Being Among Older Adults in the United States

Objectives: This article evaluates whether couples’ religious similarity is consequential for the health of older married men and women. Alternatively, we examine whether women’s religiosity alone is health-protective to their husbands. Methods: Using dyadic data from the US National Social Life, Health, and Aging Project, a representative sample of 913 individuals ages 62–91 plus their marital partners, we perform latent-class analysis to separate older couples into classes based on religious characteristics. Ordered logistic regression models are then used to assess whether different combinations of religious (dis)similarity are associated with married men and women’s well-being. Results: We find that older women in highly religious, homogamous marriages report better mental and physical health relative to women in heterogamous and secular (non-religious) marriages. No significant associations were observed for men. Discussion: Our results emphasize that religiosity is not only an individual trait—dis/similarities within a couple have important implications for older women’s well-being.
Long-term balancing selection in highly dynamic mating loci generates trans-species polymorphisms in fungi

Balancing selection, an evolutionary force that retains genetic diversity, has been detected in multiple genes and organisms, such as the sexual mating loci in fungi. In tetrapolar basidiomycete fungi, sexual type is determined by two unlinked loci, MATA and MATB. These loci are usually highly diverse, but with conserved domains. Previous studies have revealed that species of the genus Trichaptum (Hymenochaetales, Basidiomycota) possess a tetrapolar mating system, with multiple inferred alleles for MATA and MATB. Here, we sequenced a total of a hundred and eighty specimens of three Trichaptum species. We characterized the chromosomal location of MATA (chromosome 2) and MATB (chromosome 9), the molecular structure of MAT regions and their allelic richness. We found multiple MAT alleles segregating in both multiple Trichaptum specimens, and the non-Trichaptum species included for comparison. Phylogenetic analyses and various nucleotide statistics suggested that long-term balancing selection has generated trans-species polymorphisms. Mating sequences were classified in different allelic classes based on an identity threshold of higher than 86%. The observed allelic classes could potentially generate 14,560 different mating types. The inferred allelic information mirrored the outcome of in vitro crosses, thus allowing us to support the degree of allelic divergence needed for successful mating. Even with the high amount of divergence, key amino acids in functional domains are conserved. We conclude that the genetic diversity of mating in Trichaptum loci is due to long-term balancing selection that likely promote sexual outcrossing, with limited recombination and duplication activity. Our large number of sequenced specimens highlighted the importance of sequencing multiple individuals from different species to detect the mating-related genes, the mechanisms generating diversity and the evolutionary forces maintaining them.
Vegetation structure determines cyanobacterial communities during soil development across global biomes

Soil cyanobacteria play essential ecological roles and are known to experience large changes in their diversity and abundance throughout early succession. However, much less is known about how and why soil cyanobacterial communities change as soil develops from centuries to millennia, and the effects of aboveground vegetation on these communities. We combined an extensive field survey including 16 global soil chronosequences across contrasting ecosystems (from deserts to tropical forests) with molecular analyses to investigate how the diversity and abundance of soil cyanobacteria under vegetation change during soil development from hundreds to thousands of years. We show that, in most chronosequences, the abundance, species richness and community composition of soil cyanobacteria were relatively stable as soil develops (from centuries to millennia). Regardless of soil age, forest chronosequences were consistently dominated by non-photosynthetic cyanobacteria (Vampirovibrionia), while grasslands and shrublands were dominated by photosynthetic cyanobacteria. Chronosequences undergoing drastic vegetation shifts during soil development (e.g. transitions from grasslands to forests) experienced significant changes in the composition of soil cyanobacteria communities. Our results advance our understanding of the ecology of cyanobacterial classes, specially the understudied non-photosynthetic ones and highlight the key role of vegetation as a major driver of their temporal dynamics as soil develops.
Targeted combined therapy in 2D and 3D cultured MCF-7 cells using metformin and erlotinib-loaded mesoporous silica magnetic nanoparticles

Abstract Aim This research aims to develop potential therapeutic nanostructures (NSs) encapsulating metformin (MET) and erlotinib (ER) for combinational therapy in breast cancer. Methods The ER and MET, both were loaded on mesoporous silica magnetic nanoparticles conjugated with polyethylene glycol and methotrexate to achieve targeted NSs. The developed NSs were characterised using SEM, DLS, and FTIR. Afterward, MTT, Trypan blue, and DNA extraction assays were operated for biological evaluations in the 2D and 3D MCF-7 cells. Results Physicochemical approaches indicated the mean diameter of 69.4 nm ± 9.5 (PDI = 0.64), and neutral charge (2 mv) for the developed NSs. MET and ER-loaded NSs exhibited 62.56% ± 4.41 and 67.73% ± 3.03 drug release amount in pH = 5.4, respectively. MTT assay revealed that ER- and MET-loaded NSs had less metabolic activity (≈ 20%) in comparison with non-targeted NSs. Conclusion Overall, our combined ER and MET-loaded targeted NSs result in a synergistic inhibitory impact on MCF-7 cells.
Early Experiences in Switching between Monoclonal Antibodies in Patients with Nonresponsive Migraine in Spain: A Case Series

Monoclonal antibodies targeting the calcitonin gene-related peptide have been introduced into the therapeutic arsenal of migraine prophylaxis. Clinical trials report similar efficacy between them, and there is no evidence of switching to another one after failure. We aim to describe our experience in switching from erenumab to galcanezumab after therapeutic failure. We retrospectively reviewed 30 migraine patients who received monoclonal antibodies, with 15 of them switched after failure to achieve reduction in migraine days per month ≥30%. A ≥30% reduction in migraine days per month compared to baseline was observed in 8/15 (4/15 ≥ 50%) patients after switch. Some nonresponsive patients may benefit from switching between monoclonal antibodies with different therapeutic targets.
Extending the CWM approach to intraspecific trait variation: how to deal with overly optimistic standard tests?

Community weighted means (CWMs) are widely used to study the relationship between community-level functional traits and environment variation. When relationships between CWM traits and environmental variables are directly assessed using linear regression or ANOVA and tested by standard parametric tests, results are prone to inflated Type I error rates, thus producing overly optimistic results. Previous research has found that this problem can be solved by permutation tests (i.e. the max test). A recent extension of this CWM approach, that allows the inclusion of intraspecific trait variation (ITV) by partitioning information in fixed, site-specific and intraspecific CWMs, has proven popular. However, this raises the question whether the same kind of Type I error rate inflation also exists for site-specific CWM or intraspecific CWM-environment relationships. Using simulated community datasets and a real-world dataset from a subtropical montane cloud forest in Taiwan, we show that site-specific CWM-environment relationships also suffer from Type I error rate inflation, and that the severity of this inflation is negatively related to the relative ITV magnitude. In contrast, for intraspecific CWM-environment relationships, standard parametric tests have the correct Type I error rate, while being somewhat conservative, with reduced statistical power. We introduce an ITV-extended version of the max test for the ITV-extended CWM approach, which can solve the inflation problem for site-specific CWM-environment relationships, and which, without considering ITV, becomes equivalent to the “original” max test used for the CWM approach. On both simulated and real-world data, we show that this new ITV-extended max test works well across the full possible magnitude of ITV. We also provide guidelines and R codes of max test solutions for each CWM type and situation. Finally, we suggest recommendations on how to handle the results of previously published studies using the CWM approach without controlling for Type I error rate inflation.
Integrated View of Baseline Protein Expression in Human Tissues

The availability of proteomics datasets in the public domain, and in the PRIDE database in particular, has increased dramatically in recent years. This unprecedented large-scale availability of data provides an opportunity for combined analyses of datasets to get organism-wide protein abundance data in a consistent manner. We have reanalysed 24 public proteomics datasets from healthy human individuals, to assess baseline protein abundance in 31 organs. We defined tissue as a distinct functional or structural region within an organ. Overall, the aggregated dataset contains 67 healthy tissues, corresponding to 3,119 mass spectrometry runs covering 498 samples, coming from 489 individuals. We compared protein abundances between the different organs and studied the distribution of proteins across organs. We also compared the results with data generated in analogous studies. We also performed gene ontology and pathway enrichment analyses to identify organ-specific enriched biological processes and pathways. As a key point, we have integrated the protein abundance results into the resource Expression Atlas, where it can be accessed and visualised either individually or together with gene expression data coming from transcriptomics datasets. We believe this is a good mechanism to make proteomics data more accessible for life scientists.
Effect and underlying mechanism of morin on the pharmacokinetics of diclofenac sodium in rats

Abstract 1. Morin, a natural flavonol, is present in many plants. It has anti-inflammatory and immunomodulatory activities and is often used as an adjuvant treatment for arthritis. Diclofenac sodium is the first-choice drug in the treatment of rheumatoid arthritis. However, the herb-drug interaction (HDI) between morin and diclofenac sodium remains unclear. 2. The aim of the present research was to investigate whether and how morin affect the pharmacokinetic profile of diclofenac sodium. 3. The enzyme kinetic and pharmacokinetic studies showed that morin significantly accelerated the metabolism and reduced systemic exposure of diclofenac sodium. Interestingly, the effect of morin on the pharmacokinetic profile of diclofenac sodium was not in a dose-dependent manner. Therefore, the effect of morin on P-glycoprotein (P-gp) was further investigated. 4. The results implied that the influence mechanism of morin on the pharmacokinetic of diclofenac sodium might be related to CYP2C9 and P-gp. Attention should be paid to the risk of HDI between morin and diclofenac sodium in clinical practice.
Initial cognitive impairment predicts shorter survival of patients with glioblastoma

Seizures as presenting symptom of glioblastoma (GBM) are known to predict prolonged survival, whereas the clinical impact of other initial symptoms is less known. Our main objective was to evaluate the influence of different presenting symptoms on survival in a clinical setting. We also assessed lead times, tumour size and localization.