Miracle-dz/UniFAR-FTUs huggingface dataset:
Half-life of biodegradable plastics in the marine environment depends on material, habitat, and climate zone

The performance of the biodegradable plastic materials polyhydroxyalkanoate (PHA), polybutylene sebacate (PBSe) and polybutylene sebacate co-terephthalate (PBSeT), and of polyethylene (LDPE) was assessed under marine environmental conditions in a three-tier approach. Biodegradation lab tests (20 °C) were complemented by mesocosm tests (20 °C) with natural sand and seawater and by field tests in the warm-temperate Mediterranean Sea (12 – 30 °C) and in tropical Southeast Asia (29 °C) in three typical coastal scenarios. Plastic film samples were exposed in the eulittoral beach, the pelagic open water and the benthic seafloor and their disintegration monitored over time. We used statistical modelling to predict the half-life for each of the materials under the different environmental conditions to render the experimental results numerically comparable across all experimental conditions applied. The biodegradation performance of the materials differed by orders of magnitude depending on climate, habitat and material and revealed the inaccuracy to generically term a material ‘marine biodegradable’. The half-life t0.5 of a film of PHA with 85 μm thickness ranged from 54 d on the seafloor in SE Asia to 1247 d in mesocosm pelagic tests. t0.5 for PBSe (25 μm) ranged from 99 d in benthic SE Asia to 2614 d in mesocosm benthic tests, and for PBSeT t0.5 ranged from 147 d in the mesocosm eulittoral to 797 d in Mediterranean benthic field tests. For LDPE no biodegradation could be observed. These data can now be used to estimate the persistence of plastic objects should they end up in the marine environments considered here and will help to inform the life cycle (impact) assessment of plastics in the open environment.
Prefrontal-motor and somatosensory-motor cortical network interactions during reactive balance are associated with distinct aspects of balance behavior in older adults

Heightened reliance on the cerebral cortex for postural stability with aging is well-known, yet the cortical dynamics of balance control, particularly in relationship to balance function, is unclear. Here we aimed to investigate motor cortical activity in relationship to the level of balance challenge presented during reactive balance recovery, and identify circuit-specific interactions between motor cortex and prefrontal or somatosensory regions to metrics of balance function that predict fall risk. Using electroencephalography, we assessed motor cortical beta power, and beta coherence during balance reactions to perturbations in older adults. We found that individuals with greater somatosensory-motor beta coherence at baseline and lower beta power evoked over motor regions following perturbations demonstrated higher general clinical balance function. At the group-level, beta coherence between prefrontal-motor regions reduced during balance reactions. Older adults with the highest post-perturbation prefrontal-motor coherence showed greater cognitive dual-task interference and elicited stepping reactions at lower perturbation magnitudes. Our results support motor cortical beta activity as a potential biomarker for individual level of balance challenge and implicate prefrontal-and somatosensory-motor cortical networks in different aspects of balance control in older adults. Cortical network activity during balance may provide a neural target for precision-medicine efforts aimed at fall-prevention with aging.
Mouse oocytes do not contain a Balbiani body

Oocytes spend the majority of their lifetime in a primordial, dormant state. Unlike many somatic cell types and mature oocytes, the cellular and molecular biology of primordial oocytes is largely unexplored. Yet, studying their cellular biology is necessary to understand the mechanisms through which oocytes maintain cellular fitness for decades, and why they eventually fail with age. A hallmark of primordial oocytes in many species is the Balbiani body, a non-membrane bound compartment that contains the majority of mitochondria in the oocyte cytoplasm. The Balbiani body has been proposed to be essential for maintaining mitochondria in a healthy state during long-lasting dormancy, however, the architecture and function of the mammalian Balbiani body remains unknown. Here, we develop enabling methods for live-imaging based comparative characterization of Xenopus, mouse and human primordial oocytes. We show that primordial oocytes in all three vertebrate species contain active mitochondria, Golgi apparatus and lysosomes. We further demonstrate that human and Xenopus oocytes have a Balbiani body characterized by a dense accumulation of mitochondria in their cytoplasm. However, despite previous reports, we did not find a Balbiani body in mouse oocytes. Instead, we demonstrate what was previously used as a marker for the Balbiani body in mouse primordial oocytes is in fact a ring-shaped Golgi apparatus that is not functionally associated with oocyte dormancy. Our work provides the first insights into the organisation of the cytoplasm in mammalian primordial oocytes, and clarifies relative advantages and limitations of choosing different model organisms for studying oocyte dormancy.
Metabolomic profiling of pancreatic adenocarcinoma reveals fundamental clinical features

In this study, we perform the metabolomics profiling of 77 PDAC patient-derived tumor xenografts (PDTX) to investigate the relationship of metabolic profiles with overall survival (OS) in PDAC patients, tumor phenotypes and resistance to five anticancer drugs (gemcitabine, oxaliplatin, docetaxel, SN-38 and 5-Fluorouracil). We identified a metabolic signature that was able to predict the clinical outcome of PDAC patients (p < 0.001, HR=2.68 [95% CI: 1.5-4.9]). The correlation analysis showed that this metabolomic signature was significantly correlated with the PDAC molecular gradient (PAMG) (R = 0.44 and p < 0.001) indicating significant association to the transcriptomic phenotypes of tumors. Resistance score established, based on growth rate inhibition metrics using 35 PDTX-derived primary cells, allowed to identify several metabolites related to drug resistance which was globally accompanied by accumulation of several diacy-phospholipids and decrease in lysophospholipids. Interestingly, targeting glycerophospholipid synthesis improved sensitivity to the three tested cytotoxic drugs indicating that interfering with metabolism could be a promising therapeutic strategy to overcome the challenging resistance of PDAC. Short abstract Targeting metabolism of cancer cells gives a precious opportunity to overcome challenges related to the high mortality and chemoresistance in PDAC. Metabolic profiling of PDAC patient-derived tumor xenografts used in this study allowed highlighting the strong link between metabolism and both clinical outcome of the patients and chemoresistance. Metabolic signature was able to discriminate between good and bad prognosis groups of patients based on their level of key metabolites. Identification of key metabolic markers associated to chemoresistance allowed to improve sensitivity to anticancer drugs. These results provide new insights to help to predict patient survival and elaborate new combinatory therapies against chemoresistance in PDAC patients attesting of the important clinical value of this work.
Faecal metabarcoding reveals pervasive long-distance impacts of garden bird feeding

Supplementary feeding of wildlife is widespread, being undertaken by more than half of households in many countries. However, the impact that these supplemental resources have is unclear, with impacts assumed to be restricted to urban ecosystems. We reveal the pervasiveness of supplementary foodstuffs in the diet of a wild bird using metabarcoding of blue tit (Cyanistes caeruleus) faeces collected in early spring from a 220km transect in Scotland with a large urbanisation gradient. Supplementary foodstuffs were present in the majority of samples, with peanut (Arachis hypogaea) the single commonest (either natural or supplementary) dietary item. Consumption rates exhibited a distance decay from human habitation but remained high at several hundred metres from the nearest household and continued to our study limit of 1.4km distant. Supplementary food consumption was associated with a near quadrupling of blue tit breeding density and a five-day advancement of breeding phenology. We show that woodland bird species using supplementary food have increasing UK population trends, while species that don’t, and/or are outcompeted by blue tits, are likely to be declining. We suggest that the impacts of supplementary feeding are larger and more spatially extensive than currently appreciated and could be disrupting population and ecosystem dynamics.
Development and validation of a cellular host response test as an early diagnostic for sepsis

Sepsis must be diagnosed quickly to avoid morbidity and mortality. However, the clinical manifestations of sepsis are highly variable and emergency department (ED) clinicians often must make rapid, impactful decisions before laboratory results are known. We previously developed a technique that allows the measurement of the biophysical properties of white blood cells as they are stretched through a microfluidic channel. In this study we describe and validate the resultant output as a model and score – the IntelliSep Index (ISI) – that aids in the diagnosis of sepsis in patients with suspected or confirmed infection from a single blood draw performed at the time of ED presentation. By applying this technique to a high acuity cohort with a 23.5% sepsis incidence (n=307), we defined specific metrics – the aspect ratio and visco-elastic inertial response – that are more sensitive than cell size or cell count in predicting disease severity. The final model was trained and cross-validated on the high acuity cohort, and the performance and generalizability of the model was evaluated on a separate low acuity cohort with a 6.4% sepsis incidence (n=94) and healthy donors (n=72). For easier clinical interpretation, the ISI is divided into three interpretation bands of Green, Yellow, and Red that correspond to increasing disease severity. The ISI agreed with the diagnosis established by retrospective physician adjudication, and accurately identified subjects with severe illness as measured by SOFA, APACHE-II, hospital-free days, and intensive care unit admission. Measured using routinely collected blood samples, with a short run-time and no requirement for patient or laboratory information, the ISI is well suited to aid ED clinicians in rapidly diagnosing sepsis.
The Arabidopsis AAC Proteins CIL and CIA2 Are Sub-functionalized Paralogs Involved in Chloroplast Development

The Arabidopsis gene Chloroplast Import Apparatus 2 (CIA2) encodes a transcription factor that positively affects the activity of nuclear genes for chloroplast ribosomal proteins and chloroplast protein import machineries. CIA2-like (CIL) is the paralogous gene of CIA2. We generated a cil mutant by site-directed mutagenesis and compared it with cia2 and cia2cil double mutant. Phenotype of the cil mutant did not differ from the wild type under our growth conditions, except faster growth and earlier time to flowering. Compared to cia2, the cia2cil mutant showed more impaired chloroplast functions and reduced amounts of plastid ribosomal RNAs. In silico analyses predict for CIA2 and CIL a C-terminal CCT domain and an N-terminal chloroplast transit peptide (cTP). Chloroplast (and potentially nuclear) localization was previously shown for HvCMF3 and HvCMF7, the homologs of CIA2 and CIL in barley. We observed nuclear localization of CIL after transient expression in Arabidopsis protoplasts. Surprisingly, transformation of cia2 with HvCMF3, HvCMF7 or with a truncated CIA2 lacking the predicted cTP could partially rescue the pale-green phenotype of cia2. These data are discussed with respect to potentially overlapping functions between CIA2, CIL and their barley homologs and to the function of the putative cTPs of CIA2 and CIL. HIGHLIGHT The nucleus-localized CCT domain proteins CIA2 and CIL in Arabidopsis and the homologous chloroplast-localized HvCMF3 and HvCMF7 in barley retained partially overlapping functions in chloroplast development.
The Collagens DPY-17 and SQT-3 Direct Anterior-Posterior Migration of the Q Neuroblasts in C. elegans

Cell adhesion molecules and their extracellular ligands control morphogenetic events such as directed cell migration. The migration of neuroblasts and neural crest cells establishes the structure of the central and peripheral nervous systems. In C. elegans, the bilateral Q neuroblasts and their descendants undergo long-range migrations with left/right asymmetry. QR and descendants on the right migrate anteriorly, and QL and descendants on the left migrate posteriorly, despite identical patterns of cell division, cell death, and neuronal generation. The initial direction of protrusion of the Q cells relies on the left/right asymmetric function of the transmembrane receptors UNC-40/DCC and PTP-3/LAR in the Q cells. Here we show that Q cell left/right asymmetry of migration is independent of the GPA-16/Gα pathway that regulates other left/right asymmetries including nervous system L/R asymmetry. No extracellular cue has been identified that guides initial Q anterior versus posterior migration. We show that the Collagens DPY-17 and SQT-3 control initial Q direction of protrusion. Genetic interactions with UNC-40/DCC and PTP-3/LAR suggest that DPY-17 and SQT-3 drive posterior migration and might act with both receptors or in a parallel pathway. Analysis of mutants in other Collagens and extracellular matrix components indicated that general perturbation of Collagens and the ECM did not result in directional defects, and that the effect of DPY-17 and SQT-3 on Q direction is specific. DPY-17 and SQT-3 are components of the cuticle, but a role in the basement membrane cannot be excluded. Possibly, DPY-17 and SQT-3 are part of a pattern in the cuticle and/or basement membrane that is oriented to the anterior-posterior axis of the animal and that is deciphered by the Q cells in a left-right asymmetric fashion. Alternatively, DPY-17 and SQT-3 might be involved in the production or stabilization of a guidance cue that directs Q migrations. In any case, these results describe a novel role for the DPY-17 and SQT-3 Collagens in directing posterior Q neuroblast migration. Graphical Abstract
Cardiac progenitors auto-regulate second heart field cell fate via Wnt secretion

Proper heart formation requires coordinated development of two anatomically distinct groups of cells - the first and second heart fields (FHF and SHF). Given that congenital heart defects are often restricted to derivatives of the FHF or SHF, it is crucial to understand the mechanisms controlling their development. Wnt signaling has previously been implicated in SHF proliferation; however, the source of Wnts remains unknown. Through comparative gene analysis, we found upregulation of Wnts and Wnt receptor/target genes in the FHF and SHF, respectively, raising the possibility that early cardiac progenitors may secrete Wnts to influence SHF cell fate. To probe this further, we deleted Wntless (Wls), a gene required for Wnt ligand secretion, in various populations of precardiac cells. Deletion of Wls in Mesp1+ cells resulted in formation of a single chamber heart with left ventricle identity, implying compromised SHF development. This phenotype was recapitulated by deleting Wls in cells expressing Islet1, a pan-cardiac marker. Similarly, Wls deletion in cells expressing Nkx2.5, a later-expressed pan-cardiac marker, resulted in hypoplastic right ventricle, a structure derived from the SHF. However, no developmental defects were observed when deleting Wls in SHF progenitors. To gain mechanistic insights, we isolated Mesp1-lineage cells from developing embryos and performed single-cell RNA-sequencing. Our comprehensive single cell transcriptome analysis revealed that Wls deletion dysregulates developmental trajectories of both anterior and posterior SHF cells, marked by impaired proliferation and premature differentiation. Together, these results demonstrate a critical role of local precardiac mesodermal Wnts in SHF fate decision, providing fundamental insights into understanding heart field development and chamber formation. Significance Statement There is significant interest in understanding the mechanisms underlying heart formation to develop treatments and cures for patients suffering from congenital heart disease. In particular, we were interested in the intricacies of first (FHF) and second heart field (SHF) development, as many congenital heart defects present with heart field-specific etiologies. Here, we uncovered a novel relationship between specified cardiac progenitor cells and second heart field progenitors. Through genetic manipulation of Wnt secretion in developing mouse embryos, we identified a population of cardiac progenitor cells that acts as a local source of Wnts which are necessary for proper SHF development. Our single cell transcriptomic analysis of developing anterior mesoderm showed cardiac progenitor-secreted Wnts function through regulation of differentiation and proliferation among SHF progenitors. Thus, this study provides insight into the source and timing of Wnts required for SHF development, and points to the crucial role of co-developing cell populations in heart development.
Kv1.1 subunits localize to cardiorespiratory brain networks in mice where their absence induces astrogliosis and microgliosis

Cardiorespiratory collapse following a seizure is a suspected cause of sudden unexpected death in epilepsy (SUDEP), the leading cause of epilepsy-related mortality. In the commonly used Kcna1 gene knockout (Kcna1−/−) mouse model of SUDEP, cardiorespiratory profiling reveals an array of aberrant breathing patterns that could contribute to risk of seizure-related mortality. However, the brain structures mediating these respiratory abnormalities remain unknown. We hypothesize that Kv1.1 deficiency in respiratory control centers of the brain contribute to respiratory dysfunction in Kcna1−/− mice leading to increased SUDEP risk. Thus, in this study, we first used immunohistochemistry to map expression of Kv1.1 protein in cardiorespiratory brain regions of wild-type Kcna1+/+ (WT) mice. Next, GFAP and Iba1 immunostaining was used to test for the presence of astrogliosis and microgliosis, respectively, in the cardiorespiratory centers of Kcna1−/− mice, which could be indicative of seizure-related brain injury that could impair breathing. In WT type mice, we detected Kv1.1 protein in all cardiorespiratory centers examined, including the basolateral amygdala, dorsal respiratory group, dorsal motor nucleus of vagus, nucleus ambiguus, ventral respiratory column, and pontine respiratory group, as well as chemosensory centers including the retrotrapezoid and median raphae nuclei. Extensive gliosis was observed in the same areas in Kcna1−/− mice suggesting that seizure-associated brain injury could contribute to respiratory abnormalities.
A specific agonist of the orphan nuclear receptor NR2F1 suppresses metastasis through the induction of cancer cell dormancy

Disseminated tumor cells (DTCs) in secondary organs often remain dormant for a long period of time before re-awakening and growing into overt metastases. We have previously identified NR2F1/COUP-TF1, an orphan nuclear receptor, as a master regulator of tumor cell dormancy in head and neck squamous cell carcinoma (HNSCC) and other cancer types. Here we describe the identification and function of a novel NR2F1 agonist herein referred to as compound 26 (C26). C26 was found to specifically activate NR2F1 in HNSCC cells, leading to increased NR2F1 transcription and nuclear protein accumulation. C26-mediated activation of NR2F1 induced growth arrest of HNSCC PDX line and cell lines in 3D cultures in vitro and on chicken embryo chorioallantoic membrane (CAM) in vivo. The effect of C26 on growth arrest was lost when NR2F1 was knocked out by CRISPR/Cas9. C26-induced growth arrest was mediated by activation of an NR2F1-regulated dormancy program, including upregulation of cyclin-dependent kinase (CDK) inhibitor p27 and the transcription factors retinoic acid receptor β (RARβ) and Sox9. In mice bearing HNSCC PDX tumors, combined adjuvant and neo-adjuvant treatment with C26 resulted in complete inhibition of lethal lung metastasis. Mechanistic analysis showed that lung DTCs in C26-treated mice displayed an NR2F1hi/p27hi/Ki-67lo phenotype, which kept them dormant in a single-cell state preventing their outgrowth into overt metastases. Our work reveals a novel NR2F1 agonist and provides a proof of principle strategy supporting that inducing DTC dormancy using NR2F1 agonists could be used as a therapeutic strategy to prevent metastasis.
Whole-genome analysis of de novo and polymorphic retrotransposon insertions in Autism Spectrum Disorder

Retrotransposons are dynamic forces in evolutionary genomics and have been implicated as causes of Mendelian disease and hereditary cancer, but their role in Autism Spectrum Disorder (ASD) has never been systematically defined. Here, we report 86,154 polymorphic retrotransposon insertions including >60% not previously reported and 158 de novo retrotransposition events identified in whole genome sequencing (WGS) data of 2,288 families with ASD from the Simons Simplex Collection (SSC). As expected, the overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 104, and 192 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 20 births total, while the location of transposon insertions differed between ASD and unaffected individuals. ASD cases showed more de novo L1 insertions than expected in ASD genes, and we also found de novo intronic retrotransposition events in known syndromic ASD genes in affected individuals but not in controls. Additionally, we observed exonic insertions in genes with a high probability of being loss-of-function intolerant, including a likely causative exonic insertion in CSDE1, only in ASD individuals. Although de novo retrotransposition occurs less frequently than single nucleotide and copy number variants, these findings suggest a modest, but important, impact of intronic and exonic retrotransposition mutations in ASD and highlight the utility of developing specific bioinformatic tools for high-throughput detection of transposable element insertions.