Miracle-dz/UniFAR-FTUs huggingface dataset:
Prothrombin Knockdown Protects Podocytes and Reduces Proteinuria in Glomerular Disease

Chronic kidney disease (CKD) is a leading cause of death, and its progression is driven by glomerular podocyte injury and loss, manifesting as proteinuria. Proteinuria includes urinary loss of coagulation zymogens, cofactors, and inhibitors. Importantly, both CKD and proteinuria significantly increase the risk of thromboembolic disease. Prior studies demonstrated that anticoagulants reduced proteinuria in rats and that thrombin injured cultured podocytes. Herein we aimed to directly determine the influence of circulating prothrombin on glomerular pathobiology. We hypothesized that (pro)thrombin drives podocytopathy, podocytopenia, and proteinuria. Glomerular proteinuria was induced with puromycin aminonucleoside (PAN) in Wistar rats. Circulating prothrombin was either knocked down using a rat-specific antisense oligonucleotide or elevated by serial intravenous infusions of prothrombin protein, which are previously established methods to model hypo- (LoPT) and hyper-prothrombinemia (HiPT), respectively. After 10 days (peak proteinuria in this model) plasma prothrombin levels were determined, kidneys were examined for (pro)thrombin co-localization to podocytes, histology, and electron microscopy. Podocytopathy and podocytopenia were determined and proteinuria, and plasma albumin were measured. LoPT significantly reduced prothrombin colocalization to podocytes, podocytopathy, and proteinuria with improved plasma albumin. In contrast, HiPT significantly increased podocytopathy and proteinuria. Podocytopenia was significantly reduced in LoPT vs. HiPT rats. In summary, prothrombin knockdown ameliorated PAN-induced glomerular disease whereas hyper-prothrombinemia exacerbated disease. Thus, (pro)thrombin antagonism may be a viable strategy to simultaneously provide thromboprophylaxis and prevent podocytopathy-mediated CKD progression.
Metabolic and Neurobehavioral Disturbances Induced by Purine 1 Recycling Deficiency in Drosophila 2 3

Céline Petitgas1,4, Laurent Seugnet2, Amina Dulac1, Ali Mteyrek1, Rebecca Fima1, Marion 4 Strehaiano1, Joana Dagorret1, Baya Chérif-Zahar1, Sandrine Marie3, Irène Ceballos-Picot4,5 and 5 Serge Birman1,* 6 7 8 1Genes Circuits Rhythms and Neuropathology, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL 9 Research University, 75005 Paris, France 10 11 2Integrated Physiology of the Brain Arousal Systems (WAKING), Lyon Neuroscience Research 12 Centre, INSERM/CNRS/UCBL1, 69675 Bron, France 13 14 3Laboratory of Metabolic Diseases, Cliniques Universitaires Saint-Luc, Université catholique de 15 Louvain, B-1200, Brussels, Belgium 16
Hypoxia-driven deSUMOylation of EXOSC10 promotes adaptive changes in the transcriptome profile

Reduced oxygen availability (hypoxia) triggers adaptive cellular responses via hypoxia-inducible factor (HIF)-dependent transcriptional activation. Adaptation to hypoxia also involves transcription-independent processes like post-translational modifications; however, these mechanisms are poorly characterized. Investigating the involvement of protein SUMOylation in response to hypoxia, we discovered that hypoxia strongly decreases the SUMOylation of Exosome subunit 10 (EXOSC10), the catalytic subunit of the RNA exosome, in an HIF-independent manner. EXOSC10 is a multifunctional exoribonuclease enriched in the nucleolus that mediates the processing and degradation of various RNA species. We demonstrate that the ubiquitin-specific protease 36 (USP36) SUMOylates EXOSC10 and we reveal SUMO1/sentrin-specific peptidase 3 (SENP3) as the enzyme-mediating deSUMOylation of EXOSC10. Under hypoxia, EXOSC10 dissociates from USP36 and translocates from the nucleolus to the nucleoplasm concomitant with its deSUMOylation. Loss of EXOSC10 SUMOylation does not detectably affect rRNA maturation but affects the mRNA transcriptome by modulating the expression levels of hypoxia-related genes. Our data suggest that dynamic modulation of EXOSC10 SUMOylation and localization under hypoxia regulates the RNA degradation machinery to facilitate cellular adaptation to low oxygen conditions.
Mesoscale simulations predict the role of synergistic cerebellar plasticity during classical eyeblink conditioning

According to Marr’s motor learning theory, plasticity at the parallel fibre to Purkinje cells synapse (pf-PC) is the main substrate responsible for learning sensorimotor contingencies under climbing fibre control. However, the discovery of multiple forms of plasticity distributed over different cerebellar circuit synapses prompts to remap the cerebellar learning sites. Here, we have simulated classical eyeblink conditioning (CEBC) using an advanced spiking cerebellar model embedding upbound and downbound modules that are subject to multiple plasticity rules. Simulations show that synaptic plasticity regulates the cascade of precise spiking patterns spreading throughout the cerebellar cortex and cerebellar nuclei. CEBC was supported by plasticity in both the pf-PC synapses and in the feedforward inhibitory loop passing through the molecular layer interneurons (MLIs), but only the combined switch-off of both sites of plasticity compromised learning significantly. By differentially engaging climbing fibre information and related forms of synaptic plasticity, both modules contributed to generate a well-timed conditioned response, but it was the downbound module that played the major role in in this process. The outcomes of our simulations closely align with the behavioural and electrophysiological phenotypes of mutant mice suffering from cell-specific mutations that affect processing of their PC or MLI synapses. Our data highlight that a synergy of bidirectional plasticity rules distributed across the cerebellum facilitate finetuning of adaptive associative behaviours at a high spatiotemporal resolution.
Demographic and genetic impacts of powdery mildew in a young oak cohort

The demographic and genetic impacts of powdery mildew on the early stages of an oak population were studied in an ad hoc field design with two disease exposures. This enabled a detailed phenotypic monitoring of 1,733 emerging individuals from 15 progenies over nine years, and the genotyping of 68% of them. The pathogen induced high levels of seedling mortality several years after sowing, associated with reduced growth and capacity to overwinter. The probability of juvenile survival could be predicted from mean disease severity in early years and acorn weight. Fast-growing families showed the highest survival rate under both natural and protected disease exposure. Correlatively, no equalizing effect of increased powdery mildew pressure on the relative contribution of mother trees to the next generation could be detected. Contrary to a possible trade-off hypothesis between growth and defense, family height potential was not negatively related to disease resistance across the studied oak mother trees. Overall, our results suggest that in Quercus robur natural populations, infection levels (related to resistance sensu stricto) may be less determinant than growth-related tolerance to infection for the fate of seedlings. However, an equalizing effect of powdery mildew on relative oak genotype performances cannot be excluded at later stages since such an effect was already visible on height. Average genomic diversity was not significantly affected by mortality associated with powdery mildew. However, our study brings support to a deleterious effect of very low individual heterozygosity on the probability of survival across the different families. Finally, our study points to a few candidate genes for several fitness-related traits.
Sustained polyphasic sleep restriction abolishes human growth hormone release

Voluntary sleep restriction is a common phenomenon in industrialized societies aiming to increase time spent awake and thus productivity. We explored how restricting sleep to a radically polyphasic schedule affects neural, cognitive, and endocrine characteristics. Ten young healthy participants were restricted to one 30-min nap opportunity at the end of every 4 hours (i.e., 6 sleep episodes per 24 hours) without any extended core sleep window, which resulted in a cumulative sleep amount of just 2 hours per day (i.e., ∼20 min per bout). All but one participant terminated this schedule during the first three weeks. The remaining participant (a 25-year-old male) succeeded to adhere to a polyphasic schedule for 5 weeks with no apparent impairments in cognitive and psychiatric measures except for psychomotor vigilance. While in-blood cortisol or melatonin release pattern and amounts were unaltered by the polyphasic as compared to monophasic sleep, growth hormone seemed almost entirely abolished (>95% decrease), with the residual release showing a considerably changed polyphasic secretional pattern. While coarse sleep structure appeared intact during polyphasic sleep, REM sleep showed decreased oscillatory and increased aperiodic EEG activity compared to monophasic sleep. Considering the decreased vigilance, abolished growth hormone release, and neurophysiological changes observed, it is doubtful that radically polyphasic sleep schedules can subserve the different functions of sleep to a sufficient degree.
Single neuron analysis of aging associated changes in learning reveals progressive impairments in transcriptional plasticity

Molecular mechanisms underlying aging associated impairments in learning and long-term memory storage are poorly understood. Here we leveraged the single identified motor neuron L7 in Aplysia, which mediates a form of non-associative learning, sensitization of the siphon-withdraw reflex, to assess the transcriptomic correlates of aging associated changes in learning. RNAseq analysis of the single L7 motor neuron isolated following short-term or long-term sensitization training of 8,10 and 12 months old Aplysia, corresponding to mature, late mature and senescent stages, has revealed progressive impairments in transcriptional plasticity during aging. Specifically, we observed modulation of the expression of multiple lncRNAs and mRNAs encoding transcription factors, regulators of translation, RNA methylation, and cytoskeletal rearrangements during learning and their deficits during aging. Our comparative gene expression analysis also revealed the recruitment of specific transcriptional changes in two other neurons, the motor neuron L11 and the giant cholinergic neuron R2 whose roles in long-term sensitization were previously not known. Taken together, our analyses establish cell type specific progressive impairments in the expression of learning- and memory-related components of the transcriptome during aging.
A Nonlinear Model of Term Structure Dynamics

The threshold model is employed to capture the nonlinearity of the drift term in the models of the term structure of interest rates.A generalized pseudo-likelihood ratio test is introduced to test the threshold CKLS model.The results show that the threshold CKLS model can better describe the nonlinearity of the drift term than CKLS model at 0.1 significant level.
Transformer-based spatial–temporal detection of apoptotic cell death in live-cell imaging

Intravital microscopy has revolutionized live cell imaging by allowing the study of spatial-temporal cell dynamics in living animals. However, the complexity of the data generated by this technology has limited the development of effective computational tools to identify and quantify cell processes. Amongst them, apoptosis is a crucial form of regulated cell death involved in tissue homeostasis and host defense. Live-cell imaging enabled the study of apoptosis at the cellular level, enhancing our understanding of its spatial-temporal regulation. However, at present, no computational method can deliver robust detection of apoptosis in microscopy time-lapses. To overcome this limitation, we developed ADeS, a deep learning-based apoptosis detection system that employs the principle of activity recognition. We trained ADeS on extensive datasets containing more than 10,000 apoptotic instances collected both in vitro and in vivo, achieving a classification accuracy above 98% and outperforming state-of-the-art solutions. ADeS is the first method capable of detecting the location and duration of multiple apoptotic events in full microscopy time-lapses, surpassing human performance in the same task. We demonstrated the effectiveness and robustness of ADeS across various imaging modalities, cell types, and staining techniques. Finally, we employed ADeS to quantify cell survival in vitro and tissue damage in vivo, demonstrating its potential application in toxicity assays, treatment evaluation, and inflammatory dynamics. Our findings suggest that ADeS is a valuable tool for the accurate detection and quantification of apoptosis in live-cell imaging and, in particular, intravital microscopy data, providing insights into the complex spatial-temporal regulation of this process.
Case report: Meningioma associated with meningioangiomatosis mimicking invasive meningioma

Meningioangiomatosis (MA) is a rare malformation or hamartomatous lesion in the central nervous system, characterized by a plaque-like mass within the leptomeninges and cerebral cortex. An even rarer condition is MA complicated with meningiomas. We herein report a case of meningioma associated with MA that might be erroneously interpreted as a higher-grade lesion or an invasion by preoperative radiologic and postoperative histological examinations.
In silico assessment of histotripsy-induced changes in catheter-directed thrombolytic delivery

Introduction: For venous thrombosis patients, catheter-directed thrombolytic therapy is the standard-of-care to recanalize the occluded vessel. Limitations with thrombolytic drugs make the development of adjuvant treatments an active area of research. One potential adjuvant is histotripsy, a focused ultrasound therapy that lyses red blood cells within thrombus via the spontaneous generation of bubbles. Histotripsy has also been shown to improve the efficacy of thrombolytic drugs, though the precise mechanism of enhancement has not been elucidated. In this study, in silico calculations were performed to determine the contribution of histotripsy-induced changes in thrombus diffusivity to alter catheter-directed therapy. Methods: An established and validated Monte Carlo calculation was used to predict the extent of histotripsy bubble activity. The distribution of thrombolytic drug was computed with a finite-difference time domain (FDTD) solution of the perfusion-diffusion equation. The FDTD calculation included changes in thrombus diffusivity based on outcomes of the Monte Carlo calculation. Fibrin degradation was determined using the known reaction rate of thrombolytic drug. Results: In the absence of histotripsy, thrombolytic delivery was restricted in close proximity to the catheter. Thrombolytic perfused throughout the focal region for calculations that included the effects of histotripsy, resulting in an increased degree of fibrinolysis. Discussion: These results were consistent with the outcomes of in vitro studies, suggesting histotripsy-induced changes in the thrombus diffusivity are a primary mechanism for enhancement of thrombolytic drugs.
Polyphenolic flavonoid (Myricetin) upregulated proteasomal degradation mechanisms: Eliminates neurodegenerative proteins aggregation

Major neurodegenerative disorders are characterized by the formation of misfolded proteins aggregates inside or outside the neuronal cells. Previous studies suggest that aberrant proteins aggregates play a critical role in protein homeostasis imbalance and failure of protein quality control (PQC) mechanism, leading to disease conditions. However, we still do not understand the precise mechanisms of PQC failure and cellular dysfunctions associated with neurodegenerative diseases caused by the accumulation of protein aggregates. Here, we show that Myricetin, a flavonoid, can eliminate various abnormal proteins from the cellular environment via modulating endogenous levels of Hsp70 chaperone and quality control (QC)‐E3 ubiquitin ligase E6‐AP. We have observed that Myricetin treatment suppresses the aggregation of different aberrant proteins. Myricetin also enhances the elimination of various toxic neurodegenerative diseases associated proteins from the cells, which could be reversed by the addition of putative proteasome inhibitor (MG132). Remarkably, Myricetin can also stabilize E6‐AP and reduce the misfolded proteins inclusions, which further alleviates cytotoxicity. Taken together these findings suggested that new mechanistic and therapeutic insights based on small molecules mediated regulation of disturbed protein quality control mechanism, which may result in the maintenance of the state of proteostasis.
Expression and role of the immune checkpoint regulator PD-L1 in the tumor-stroma interplay of pancreatic ductal adenocarcinoma

Introduction Immune checkpoint inhibitors (ICI), e.g., targeting programmed cell death protein 1-ligand 1 (PD-L1) or its receptor PD-1, have markedly improved the therapy of many cancers but so far failed in pancreatic ductal adenocarcinoma (PDAC). Macrophages represent one of the most abundant immune cell populations within the tumor microenvironment (TME) of PDAC being able to either support or restrain tumor progression depending on their phenotype. To better understand treatment failure of PD-L1/PD-1 inhibitors in PDAC, this study examined PD-L1 expression in the context of a dynamic TME in PDAC with a particular focus on the impact of macrophages. Methods Formalin-fixed and paraffin embedded tissue samples of primary PDAC tissues and corresponding liver metastases were used for immunohistochemical analyses. Serial sections were stained with antibodies detecting Pan-Cytokeratin, CD68, CD163, CD8, and PD-L1.To investigate whether the PD-1/PD-L1 axis and macrophages contribute to immune escape of PDAC cells, a stroma enriched 3D spheroid coculture model was established in vitro, using different PDAC cell lines and macrophages subtypes as well as CD8+ T cells. Functional and flow cytometry analyses were conducted to characterize cell populations. Results Immunohistochemical analyses revealed that PD-L1 is mainly expressed by stroma cells, including macrophages and not PDAC cells in primary PDAC tissues and corresponding liver metastases. Notably, high local abundance of macrophages and strong PD-L1 staining were commonly found at invasion fronts of tumoral lesions between CD8+ T cells and tumor cells. In order to investigate whether PD-L1 expressing macrophages impact the response of PDAC cells to treatment with PD-L1/PD-1 inhibitors, we developed a spheroid model comprising two different PDAC cell lines and different ratios of in vitro differentiated primary M1- or M2-like polarized macrophages. In line with our in situ findings, high PD-L1 expression was observed in macrophages rather than PDAC cells, which was further increased by the presence of PDAC cells. The effector phenotype of co-cultured CD8+ T cells exemplified by expression of activation markers and release of effector molecules was rather enhanced by PDAC macrophage spheroids, particularly with M1-like macrophages compared to mono-culture spheroids. However, this was not associated with enhanced PDAC cell death. ICI treatment with either Durvalumab or Pembrolizumab alone or in combination with Gemcitabine hardly affected the effector phenotype of CD8+ T cells along with PDAC cell death. Thus, despite strong PD-L1 expression in macrophages, ICI treatment did not result in an enhanced activation and cytotoxic phenotype of CD8+ T cells. Conclusion Overall, our study revealed novel insights into the interplay of PDAC cells and macrophages in the presence of ICI.
The conscious processing of emotion in depression disorder: a meta-analysis of neuroimaging studies

Background Depression is generally accompanied by a disturbed conscious processing of emotion, which manifests as a negative bias to facial/voice emotion information and a decreased accuracy in emotion recognition tasks. Several studies have proved that abnormal brain activation was responsible for the deficit function of conscious emotion recognition in depression. However, the altered brain activation related to the conscious processing of emotion in depression was incongruent among studies. Therefore, we conducted an activation likelihood estimation (ALE) analysis to better understand the underlying neurophysiological mechanism of conscious processing of emotion in depression. Method Electronic databases were searched using the search terms “depression,” “emotion recognition,” and “neuroimaging” from inceptions to April 10th, 2023. We retrieved trials which explored the neuro-responses of depressive patients to explicit emotion recognition tasks. Two investigators independently performed literature selection, data extraction, and risk of bias assessment. The spatial consistency of brain activation in conscious facial expressions recognition was calculated using ALE. The robustness of the results was examined by Jackknife sensitivity analysis. Results We retrieved 11,365 articles in total, 28 of which were included. In the overall analysis, we found increased activity in the middle temporal gyrus, superior temporal gyrus, parahippocampal gyrus, and cuneus, and decreased activity in the superior temporal gyrus, inferior parietal lobule, insula, and superior frontal gyrus. In response to positive stimuli, depressive patients showed hyperactivity in the medial frontal gyrus, middle temporal gyrus, and insula (uncorrected p < 0.001). When receiving negative stimuli, a higher activation was found in the precentral gyrus, middle frontal gyrus, precuneus, and superior temporal gyrus (uncorrected p < 0.001). Conclusion Among depressive patients, a broad spectrum of brain areas was involved in a deficit of conscious emotion processing. The activation of brain regions was different in response to positive or negative stimuli. Due to potential clinical heterogeneity, the findings should be treated with caution. Systematic review registration https://inplasy.com/inplasy-2022-11-0057/, identifier: 2022110057.
Research progress in physiological effects of resistant substances of Urtica dioica L. on animal performance and feed conversion

Several members of family Urticaceae are mainly found in the temperate and subtropical zones of the Northern Hemisphere and are important medicinal plants. Among them, Urtica dioica L. (Urticaceae) is an annual or perennial herb that has been used for feeding and medicinal purposes since long time and is the most exploited species of Urticaceae. Recently, it has received attention to be used as animal feed, as its fresh leaves fed to animals in moderate, dried, and other forms. This review details the advantages of U. dioica as an alternative feed in terms of germplasm specificity, nutritional composition, and feed application status. Its roots, stems, leaves, and seeds are rich in active ingredients. It has also been found to have anticancer effects through antioxidant action and promotion of apoptosis of cancer cells. In shady conditions, U. dioica is highly adaptable while under stressful conditions of drought; it also reduces light absorption and ensures carbon assimilation through light energy conversion efficiency. Therefore, it can be added to animal diets as a suitable feed to reduce costs and improve economic efficiency. This paper investigates the feasibility of using U. dioica as a feed and systematically presents the progress of research and exploitation of U. dioica.