Miracle-dz/UniFAR-FTUs huggingface dataset:
Misoprostol Treatment Prevents Hypoxia-Induced Cardiac Dysfunction, Aberrant Cardiomyocyte Mitochondrial Dynamics and Permeability Transition Through Bnip3 Phosphorylation

Systemic hypoxia, a major complication associated with reduced gestational time, affects more 60% of preterm infants and is a known driver of hypoxia-induced Bcl-2-like 19kDa-interacting protein 3 (Bnip3) expression in the neonatal heart. At the level of the cardiomyocyte, Bnip3 activity plays a prominent role in the evolution of necrotic cell death, disrupting subcellular calcium homeostasis and initiating mitochondrial permeability transition (MPT). Emerging evidence suggests both a cardioprotective role for protein kinase A (PKA) through stimulatory prostaglandin (PG) E1 signalling during prolonged periods of hypoxia, and a cytoprotective role for Bnip3 phosphorylation, indicating that post-translational modifications of Bnip3 may be a point of convergence for these two protective pathways. Using a combination of in vivo and multiple cell models, including human iPSC-derived cardiomyocytes, we tested if the PGE1 analogue misoprostol is cardioprotective during neonatal hypoxic injury by altering the phosphorylation status of Bnip3. Here we report that hypoxia exposure significantly increases Bnip3 expression, mitochondrial-fragmentation, -ROS, -calcium accumulation and -permeability transition, while reducing mitochondrial membrane potential, all of which were restored to control levels with the addition of misoprostol, despite elevated Bnip3 protein expression. Through both gain- and loss-of-function genetic studies we further show that misoprostol-induced protection directly affects Bnip3, preventing mitochondrial perturbations. We demonstrate that this is a result of PG EP4 receptor signalling, PKA activation, and direct Bnip3 phosphorylation at threonine-181. Furthermore, when this PKA phosphorylation site within Bnip3 is neutralized, the protective misoprostol effect is lost. We also provide evidence that misoprostol traffics Bnip3 away from the ER through a physical interaction with 14-3-3β, thereby preventing aberrant ER calcium release and MPT. In vivo studies further demonstrate that misoprostol treatment increases Bnip3 phosphorylation at threonine-181 in the mouse heart, while both misoprostol treatment and genetic ablation of Bnip3 prevented hypoxia-induced reductions in contractile function. Taken together, our results demonstrate a foundational role for Bnip3 phosphorylation in the molecular regulation of cardiomyocyte contractile and metabolic dysfunction and identifies EP4 signaling as a potential pharmacological mechanism to prevent hypoxia-induced neonatal cardiac injury. Graphical Abstract
Errors in Human-Robot Interactions and Their Effects on Robot Learning

During human-robot interaction, errors will occur. Hence, understanding the effects of interaction errors and especially the effect of prior knowledge on robot learning performance is relevant to develop appropriate approaches for learning under natural interaction conditions, since future robots will continue to learn based on what they have already learned. In this study, we investigated interaction errors that occurred under two learning conditions, i.e., in the case that the robot learned without prior knowledge (cold-start learning) and in the case that the robot had prior knowledge (warm-start learning). In our human-robot interaction scenario, the robot learns to assign the correct action to a current human intention (gesture). Gestures were not predefined but the robot had to learn their meaning. We used a contextual-bandit approach to maximize the expected payoff by updating (a) the current human intention (gesture) and (b) the current human intrinsic feedback after each action selection of the robot. As an intrinsic evaluation of the robot behavior we used the error-related potential (ErrP) in the human electroencephalogram as reinforcement signal. Either gesture errors (human intentions) can be misinterpreted by incorrectly captured gestures or errors in the ErrP classification (human feedback) can occur. We investigated these two types of interaction errors and their effects on the learning process. Our results show that learning and its online adaptation was successful under both learning conditions (except for one subject in cold-start learning). Furthermore, warm-start learning achieved faster convergence, while cold-start learning was less affected by online changes in the current context.
Pax7 pioneer factor action requires both paired and homeo DNA binding domains

The pioneer transcription factor Pax7 contains two DNA binding domains (DBD), a paired and a homeo domain. Previous work on Pax7 and the related Pax3 had shown that each DBD can bind a cognate DNA sequence, thus defining two targets of binding and possibly modalities of action. Genomic targets of Pax7 pioneer action leading to chromatin opening are enriched for composite DNA target sites containing juxtaposed binding sites for both paired and homeo domains. The present work investigated the implication of both DBDs in pioneer action. We now show that the composite sequence is a higher affinity Pax7 binding site compared to either paired or homeo binding sites and that efficient binding to this site involves both DBDs. We also show that a Pax7 monomer binds composite sites and that methylation of cytosines within the binding site does not affect binding, which is consistent with pioneer action exerted at methylated DNA sites within nucleosomal heterochromatin. Finally, introduction of single amino acid mutations in either the paired or homeo domain that impair binding to cognate DNA sequences showed that both DBDs must be intact for pioneer action. In contrast, only the paired domain is required for low affinity binding of heterochromatin sites. Thus, Pax7 pioneer action on heterochromatin requires unique protein:DNA interactions that are more complex compared to its simpler DNA binding modalities at accessible enhancer target sites. Significance Statement Pioneer transcription factors have the unique ability to recognize DNA target sites within closed heterochromatin and to trigger chromatin opening. Only a fraction of the heterochromatin recruitment sites of pioneers are subject to chromatin opening. The molecular basis for this selectivity is unknown and the present work addressed the importance of DNA sequence affinity for selection of sites to open. The pioneering ability of the pioneer factor Pax7 is not strictly determined by affinity or DNA sequence of binding sites, nor by number or methylation status of DNA sites. Mutation analyses showed that recruitment to heterochromatin is primarily dependent on the Pax7 paired domain whereas the ability to open chromatin requires both paired and homeo DNA binding domains.
Avian Feeding Preferences of Culex pipiens and Culiseta spp. Along an Urban-to-Wild Gradient in Northern Spain

Mosquitoes (Diptera: Culicidae) are regarded as annoying biting pests and vectors of disease-causing agents to humans and other vertebrates worldwide. Factors that affect their distribution and host choice are not well understood. Here, we assessed the species abundance, community composition, and feeding patterns of mosquitoes in an urban-to-wild habitat gradient in northern Spain. Adult mosquitoes from four habitats (urban, periurban, rural, and wild) were collected by aspiration from mid-July to mid-September, 2019. Thirteen species were represented among the 268 specimens (132 females and 136 males) trapped, including six new records reported for the first time in the region. Culex pipiens was the most abundant species in all habitats except in the wild, where Culex territans was dominant. The highest mosquito diversity was recorded in the wild habitat [species richness (S) = 10 and Shannon/Margalef-Diversity Indices (H’/MI = 1.51/1.36)] and the lowest in the urban habitat (S = 3; H’/MI = 0.24/0.41). Blood-engorged specimens (n = 65) represented 49.2% of the total female collections. Eighty percent of the blood-meals (n = 52) were successfully identified based on cytochrome c oxidase I subunit (COI) DNA barcoding. Nine species of birds were identified in blood meals from the three ecological forms of Cx. pipiens (n = 48), Culiseta fumipennis (n = 3), and Culiseta morsitans (n = 1) collected along the four sampling habitats. Four dominant bird species were recorded in Cx. pipiens, i.e., Parus major (35.4%), Turdus merula (18.7%), Pica pica (18.7%), and Passer domesticus (10.4%). Despite the availability of dog and human hosts in the sampling sites located in the urban habitat, Cx. pipiens seemed to have a preference to feed on birds. Culiseta fumipennis blood-meal host records are reported for first time in Europe. These findings on mosquito blood-feeding preferences and habitat community changes will help to better understand vector-host associations and pathogen transmission paths.
Plant–Plant Communication: Is There a Role for Volatile Damage-Associated Molecular Patterns?

Damage-associated molecular patterns (DAMPs) are an ancient form of tissue-derived danger or alarm signals that initiate cellular signaling cascades, which often initiate defined defense responses. A DAMP can be any molecule that is usually not exposed to cells such as cell wall components, peptides, nucleic acid fragments, eATP and other compounds. DAMPs might be revealed upon tissue damage or during attack. Typically, DAMPs are derived from the injured organism. Almost all eukaryotes can generate and respond to DAMPs, including plants. Besides the molecules mentioned, certain volatile organic compounds (VOCs) can be considered as DAMPs. Due to their chemical nature, VOCs are supposed to act not only locally and systemically in the same plant but also between plants. Here, we focus on damage-induced volatiles (DIVs) that might be regarded as DAMPs; we will review their origin, chemical nature, physiochemical properties, biological relevance and putative function in plant–plant communications. Moreover, we discuss the possibility to use such airborne DAMPs as eco-friendly compounds to stimulate natural defenses in agriculture in order to avoid pesticides.
Exercise does not enhance short-term deprivation-induced ocular dominance plasticity: evidence from dichoptic surround suppression

The input from the two eyes is combined in the brain. In this combination, the relative strength of the input from each eye is determined by the ocular dominance. Recent work has shown that this dominance can be temporarily shifted. Covering one eye with an eye patch for a few hours makes its contribution stronger. It has been proposed that this shift can be enhanced by exercise. Here, we test this hypothesis using a dichoptic surround suppression task, and with exercise performed according to American College of Sport Medicine guidelines. We measured detection thresholds for patches of sinusoidal grating shown to one eye. When an annular mask grating was shown simultaneously to the other eye, thresholds were elevated. The difference in the elevation found in each eye is our measure of relative eye dominance. We made these measurements before and after 120 minutes of monocular deprivation (with an eye patch). In the control condition, subjects rested during this time. For the exercise condition, 30 minutes of exercise were performed at the beginning of the patching period. This was followed by 90 minutes of rest. We find that patching results in a shift in ocular dominance that can be measured using dichoptic surround suppression. However, we find no effect of exercise on the magnitude of this shift. We further performed a meta-analysis on the four studies that have examined the effects of exercise on the dominance shift. Looking across these studies, we find no evidence for such an effect.
Feed Restriction in Broiler Chickens Production: A Review

The feed restriction programs is on of the main techniques in growth curve manipulation for increasing production efficiency in broiler chicken. Quantities and qualitative feed restriction are procedures that can be used to manipulate the feeding strategies of poultry in order to decrease growth and metabolic rate to some extent and so alleviate the incidence of some metabolic diseases such as ascites, lameness, mortality and sudden death syndrome and so improving feed conversion and reducing feed cost. Also to produce a leaner bird and reduce the unfavorable effects of fat on human health and to reduce fat deposition in broiler carcasses using of feed restriction programs can be profitable in broiler chickens production. This article surveys new findings in feed restriction of broilers and evaluates the application of feed restriction methods to broiler chicken production.
Modulation of Transient receptor potential melastatin 3 by protons through its intracellular binding sites

Transient receptor potential melastatin 3 channel (TRPM3) is a calcium-permeable nonselective cation channel that plays an important role in modulating glucose homeostasis in the pancreatic beta cells. However, how TRPM3 is regulated under physiological and pathological conditions is poorly understood. In this study, we found that both intracellular and extracellular protons block TRPM3 through its intracellular binding sites. We demonstrated that external protons indirectly block TRPM3, whereas internal protons inhibit TRPM3 directly with an inhibitory pH50 of 6.9 ± 0.11. We identified three titratable residues, D1059, D1062, and D1073, at the inner vestibule of the channel pore that contribute to pH sensitivity. The mutation of D1073Q reduces TRPM3 current intensity and pH sensitivity; Replacement of Asp 1073 by Gln 1073 changes the reduction of TRPM3 outward current by low external pH 5.5, from 62 ± 3 % in WT to 25 ± 6.0 % in D1073Q. These results indicate that D1073 is not only essential for intracellular pH sensitivity, but it is also crucial for TRPM3 channel gating. In addition, a single mutation of D1059 or D1062 enhances pH sensitivity. In summary, our findings provide a novel molecular determinant for pH regulation of TRPM3. The inhibition of TRPM3 by protons may indicate an endogenous mechanism governing TRPM3 gating and its physiological/ pathological functions.
The Role of microRNAs in Heart Failure: A Systematic Review

MicroRNAs are highly investigated for their role in the pathogenesis of cardiovascular diseases. Nevertheless, evidence for clinical implementation is still lacking. In our systematic review, we evaluated the potential of microRNAs as pathophysiological and diagnostic biomarkers of heart failure. We identified 72 differentially expressed microRNA molecules among groups of heart failure patients and control groups by searching the PubMed database. We did not identify a substantial overlap of differentially expressed microRNAs among different studies; only five microRNAs (miR-1228, miR-122, miR-423-5p, miR-142-3p, and exosomal miR-92b-5p) were differentially expressed in more than one included study. Gene set enrichment analysis, based on the gene targets of microRNAs presented in the included studies, showed that gene targets of differentially expressed microRNAs were enriched in the MAPK, TGFβ, PI3K-Akt, and IL-2 signaling pathways, as well as apoptosis pathway, p53 activity regulation, and angiogenesis pathway. Results of our systematic review show that there is currently insufficient support for the use of any of the presented microRNAs as pathophysiological or prognostic biomarkers in the clinical setting.
Activity-Dependent Remodeling of Synaptic Protein Organization Revealed by High Throughput Analysis of STED Nanoscopy Images

The organization of proteins in the apposed nanodomains of pre- and postsynaptic compartments is thought to play a pivotal role in synaptic strength and plasticity. As such, the alignment between pre- and postsynaptic proteins may regulate, for example, the rate of presynaptic release or the strength of postsynaptic signaling. However, the analysis of these structures has mainly been restricted to subsets of synapses, providing a limited view of the diversity of synaptic protein cluster remodeling during synaptic plasticity. To characterize changes in the organization of synaptic nanodomains during synaptic plasticity over a large population of synapses, we combined STimulated Emission Depletion (STED) nanoscopy with a Python-based statistical object distance analysis (pySODA), in dissociated cultured hippocampal circuits exposed to treatments driving different forms of synaptic plasticity. The nanoscale organization, characterized in terms of coupling properties, of presynaptic (Bassoon, RIM1/2) and postsynaptic (PSD95, Homer1c) scaffold proteins was differently altered in response to plasticity-inducing stimuli. For the Bassoon - PSD95 pair, treatments driving synaptic potentiation caused an increase in their coupling probability, whereas a stimulus driving synaptic depression had an opposite effect. To enrich the characterization of the synaptic cluster remodeling at the population level, we applied unsupervised machine learning approaches to include selected morphological features into a multidimensional analysis. This combined analysis revealed a large diversity of synaptic protein cluster subtypes exhibiting differential activity-dependent remodeling, yet with common features depending on the expected direction of plasticity. The expanded palette of synaptic features revealed by our unbiased approach should provide a basis to further explore the widely diverse molecular mechanisms of synaptic plasticity.
VISTA Re-programs Macrophage Biology Through the Combined Regulation of Tolerance and Anti-inflammatory Pathways

We present the novel finding that V-domain Ig suppressor of T cell activation (VISTA) negatively regulates innate inflammation through the transcriptional and epigenetic re-programming of macrophages. Representative of VISTA re-programming is the ability of VISTA agonistic antibodies to augment LPS tolerance and reduce septic shock lethality in mice. This anti-inflammatory effect of anti-VISTA was mimicked in vitro demonstrating that anti-VISTA treatment caused a significant reduction in LPS-induced IL-12p40, IL-6, CXCL2, and TNF; all hallmark pro-inflammatory mediators of endotoxin shock. Even under conditions that typically “break” LPS tolerance, VISTA agonists sustained a macrophage anti-inflammatory profile. Analysis of the proteomic and transcriptional changes imposed by anti-VISTA show that macrophage re-programming was mediated by a composite profile of mediators involved in both macrophage tolerance induction (IRG1, miR221, A20, IL-10) as well as transcription factors central to driving an anti-inflammatory profile (e.g., IRF5, IRF8, NFKB1). These findings underscore a novel and new activity of VISTA as a negative checkpoint regulator that induces both tolerance and anti-inflammatory programs in macrophages and controls the magnitude of innate inflammation in vivo.
Evolution and Conservation of Bordetella Intracellular Survival in Eukaryotic Host Cells

The classical bordetellae possess several partially characterized virulence mechanisms that are studied in the context of a complete extracellular life cycle in their mammalian hosts. Yet, classical bordetellae have repeatedly been reported within dendritic cells (DCs) and alveolar macrophages in clinical samples, and in vitro experiments convincingly demonstrate that the bacteria can survive intracellularly within mammalian phagocytic cells, an ability that appears to have descended from ancestral progenitor species that lived in the environment and acquired the mechanisms to resist unicellular phagocytic predators. Many pathogens, including Mycobacterium tuberculosis, Salmonella enterica, Francisella tularensis, and Legionella pneumophila, are known to parasitize and multiply inside eukaryotic host cells. This strategy provides protection, nutrients, and the ability to disseminate systemically. While some work has been dedicated at characterizing intracellular survival of Bordetella pertussis, there is limited understanding of how this strategy has evolved within the genus Bordetella and the contributions of this ability to bacterial pathogenicity, evasion of host immunity as well as within and between-host dissemination. Here, we explore the mechanisms that control the metabolic changes accompanying intracellular survival and how these have been acquired and conserved throughout the evolutionary history of the Bordetella genus and discuss the possible implications of this strategy in the persistence and reemergence of B. pertussis in recent years.
Cellular Protein Quality Control in Diabetic Cardiomyopathy: From Bench to Bedside

Heart failure is a serious comorbidity and the most common cause of mortality in diabetes patients. Diabetic cardiomyopathy (DCM) features impaired cellular structure and function, culminating in heart failure; however, there is a dearth of specific clinical therapy for treating DCM. Protein homeostasis is pivotal for the maintenance of cellular viability under physiological and pathological conditions, particularly in the irreplaceable cardiomyocytes; therefore, it is tightly regulated by a protein quality control (PQC) system. Three evolutionarily conserved molecular processes, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and autophagy, enhance protein turnover and preserve protein homeostasis by suppressing protein translation, degrading misfolded or unfolded proteins in cytosol or organelles, disposing of damaged and toxic proteins, recycling essential amino acids, and eliminating insoluble protein aggregates. In response to increased cellular protein demand under pathological insults, including the diabetic condition, a coordinated PQC system retains cardiac protein homeostasis and heart performance, on the contrary, inappropriate PQC function exaggerates cardiac proteotoxicity with subsequent heart dysfunction. Further investigation of the PQC mechanisms in diabetes propels a more comprehensive understanding of the molecular pathogenesis of DCM and opens new prospective treatment strategies for heart disease and heart failure in diabetes patients. In this review, the function and regulation of cardiac PQC machinery in diabetes mellitus, and the therapeutic potential for the diabetic heart are discussed.