Galectins in epithelial-mesenchymal transition: roles and mechanisms contributing to tissue repair, fibrosis and cancer metastasis.

Galectins are soluble glycan-binding proteins that interact with a wide range of glycoproteins and glycolipids and modulate a broad spectrum of physiological and pathological processes. The expression and subcellular localization of different galectins vary among tissues and cell types and change during processes of tissue repair, fibrosis and cancer where epithelial cells loss differentiation while acquiring migratory mesenchymal phenotypes. The epithelial-mesenchymal transition (EMT) that occurs in the context of these processes can include modifications of glycosylation patterns of glycolipids and glycoproteins affecting their interactions with galectins. Moreover, overexpression of certain galectins has been involved in the development and different outcomes of EMT. This review focuses on the roles and mechanisms of Galectin-1 (Gal-1), Gal-3, Gal-4, Gal-7 and Gal-8, which have been involved in physiologic and pathogenic EMT contexts.

Progress and Challenge of Sensors for Dairy Food Safety Monitoring.

One of the most consumed foods is milk and milk products, and guaranteeing the suitability of these products is one of the major concerns in our society. This has led to the development of numerous sensors to enhance quality controls in the food chain. However, this is not a simple task, because it is necessary to establish the parameters to be analyzed and often, not only one compound is responsible for food contamination or degradation. To attempt to address this problem, a multiplex analysis together with a non-directed (e.g., general parameters such as pH) analysis are the most relevant alternatives to identifying the safety of dairy food. In recent years, the use of new technologies in the development of devices/platforms with optical or electrochemical signals has accelerated and intensified the pursuit of systems that provide a simple, rapid, cost-effective, and/or multiparametric response to the presence of contaminants, markers of various diseases, and/or indicators of safety levels. However, achieving the simultaneous determination of two or more analytes in situ, in a single measurement, and in real time, using only one working 'real sensor', remains one of the most daunting challenges, primarily due to the complexity of the sample matrix. To address these requirements, different approaches have been explored. The state of the art on food safety sensors will be summarized in this review including optical, electrochemical, and other sensor-based detection methods such as magnetoelastic or mass-based sensors.

Efficacy and safety of biological treatment for inflammatory bowel disease in elderly patients: Results from a GETECCU cohort.

INTRODUCTION: Biological therapies used for the treatment of inflammatory bowel disease (IBD) have shown to be effective and safe, although these results were obtained from studies involving mostly a young population, who are generally included in clinical trials. The aim of our study was to determine the efficacy and safety of the different biological treatments in the elderly population. METHODS: Multicenter study was carried out in the GETECCU group. Patients diagnosed with IBD and aged over 65 years at the time of initiating biological therapy (infliximab, adalimumab, golimumab, ustekinumab or vedolizumab) were retrospectively included. Among the patients included, clinical response was assessed after drug induction (12 weeks of treatment) and at 52 weeks. Patients' colonoscopy data in week 52 were assessment, where available. Regarding complications, development of oncological events during follow-up and infectious processes occurring during biological treatment were collected (excluding bowel infection by cytomegalovirus). RESULTS: A total of 1090 patients were included. After induction, at approximately 12-14 weeks of treatment, 419 patients (39.6%) were in clinical remission, 502 patients (47.4%) had responded without remission and 137 patients (12.9%) had no response. At 52 weeks of treatment 442 patients (57.1%) had achieved clinical remission, 249 patients had responded without remission (32.2%) and 53 patients had no response to the treatment (6.8%). Before 52 weeks, 129 patients (14.8%) had discontinued treatment due to inefficacy, this being significantly higher (p<0.0001) for Golimumab - 9 patients (37.5%) - compared to the other biological treatments analyzed. With respect to tumor development, an oncological event was observed in 74 patients (6.9%): 30 patients (8%) on infliximab, 23 (7.14%) on adalimumab, 3 (11.1%) on golimumab, 10 (6.4%) on ustekinumab, and 8 (3.8%) on vedolizumab. The incidence was significantly lower (p=0.04) for the vedolizumab group compared to other treatments. As regards infections, these occurred in 160 patients during treatment (14.9%), with no differences between the different biologicals used (p=0.61): 61 patients (19.4%) on infliximab, 39 (12.5%) on adalimumab, 5 (17.8%) on golimumab, 22 (14.1%) on ustekinumab, and 34 (16.5%) on vedolizumab. CONCLUSIONS: Biological drug therapies have response rates in elderly patients similar to those described in the general population, Golimumab was the drug that was discontinued most frequently due to inefficacy. In our experience, tumor development was more frequent in patients who used anti-TNF therapies compared to other targets, although its incidence was generally low and that this is in line with younger patients based on previous literature.

Phosphatidic acid-PKA signaling regulates p38 and ERK1/2 functions in ligand-independent EGFR endocytosis.

Ligand-independent epidermal growth factor receptor (EGFR) endocytosis is inducible by a variety of stress conditions converging upon p38 kinase. A less known pathway involves phosphatidic acid (PA) signaling toward the activation of type 4 phosphodiesterases (PDE4) that decrease cAMP levels and protein kinase A (PKA) activity. This PA/PDE4/PKA pathway is triggered with propranolol used to inhibit PA hydrolysis and induces clathrin-dependent and clathrin-independent endocytosis, followed by reversible accumulation of EGFR in recycling endosomes. Here we give further evidence of this signaling pathway using biosensors of PA, cAMP, and PKA in live cells and then show that it activates p38 and ERK1/2 downstream the PKA inhibition. Clathrin-silencing and IN/SUR experiments involved the activity of p38 in the clathrin-dependent route, while ERK1/2 mediates clathrin-independent EGFR endocytosis. The PA/PDE4/PKA pathway selectively increases the EGFR endocytic rate without affecting LDLR and TfR constitute endocytosis. This selectiveness is probably because of EGFR phosphorylation, as detected in Th1046/1047 and Ser669 residues. The EGFR accumulates at perinuclear recycling endosomes colocalizing with TfR, fluorescent transferrin, and Rab11, while a small proportion distributes to Alix-endosomes. A non-selective recycling arrest includes LDLR and TfR in a reversible manner. The PA/PDE4/PKA pathway involving both p38 and ERK1/2 expands the possibilities of EGFR transmodulation and interference in cancer.

Thermophilic Carboxylesterases from Hydrothermal Vents of the Volcanic Island of Ischia Active on Synthetic and Biobased Polymers and Mycotoxins.

Hydrothermal vents are geographically widespread and host microorganisms with robust enzymes useful in various industrial applications. We examined microbial communities and carboxylesterases of two terrestrial hydrothermal vents of the volcanic island of Ischia (Italy) predominantly composed of Firmicutes, Proteobacteria, and Bacteroidota. High-temperature enrichment cultures with the polyester plastics polyhydroxybutyrate and polylactic acid (PLA) resulted in an increase of Thermus and Geobacillus species and to some extent Fontimonas and Schleiferia species. The screening at 37 to 70°C of metagenomic fosmid libraries from above enrichment cultures identified three hydrolases (IS10, IS11, and IS12), all derived from yet-uncultured Chloroflexota and showing low sequence identity (33 to 56%) to characterized enzymes. Enzymes expressed in Escherichia coli exhibited maximal esterase activity at 70 to 90°C, with IS11 showing the highest thermostability (90% activity after 20-min incubation at 80°C). IS10 and IS12 were highly substrate promiscuous and hydrolyzed all 51 monoester substrates tested. Enzymes were active with PLA, polyethylene terephthalate model substrate, and mycotoxin T-2 (IS12). IS10 and IS12 had a classical α/ß-hydrolase core domain with a serine hydrolase catalytic triad (Ser155, His280, and Asp250) in their hydrophobic active sites. The crystal structure of IS11 resolved at 2.92 Å revealed the presence of a N-terminal ß-lactamase-like domain and C-terminal lipocalin domain. The catalytic cleft of IS11 included catalytic Ser68, Lys71, Tyr160, and Asn162, whereas the lipocalin domain enclosed the catalytic cleft like a lid and contributed to substrate binding. Our study identified novel thermotolerant carboxylesterases with a broad substrate range, including polyesters and mycotoxins, for potential applications in biotechnology. IMPORTANCE High-temperature-active microbial enzymes are important biocatalysts for many industrial applications, including recycling of synthetic and biobased polyesters increasingly used in textiles, fibers, coatings and adhesives. Here, we identified three novel thermotolerant carboxylesterases (IS10, IS11, and IS12) from high-temperature enrichment cultures from Ischia hydrothermal vents and incubated with biobased polymers. The identified metagenomic enzymes originated from uncultured Chloroflexota and showed low sequence similarity to known carboxylesterases. Active sites of IS10 and IS12 had the largest effective volumes among the characterized prokaryotic carboxylesterases and exhibited high substrate promiscuity, including hydrolysis of polyesters and mycotoxin T-2 (IS12). Though less promiscuous than IS10 and IS12, IS11 had a higher thermostability with a high temperature optimum (80 to 90°C) for activity and hydrolyzed polyesters, and its crystal structure revealed an unusual lipocalin domain likely involved in substrate binding. The polyesterase activity of these enzymes makes them attractive candidates for further optimization and potential application in plastics recycling.

Chronic exposure to inorganic arsenic and fluoride induces redox imbalance, inhibits the transsulfuration pathway, and alters glutamate receptor expression in the brain, resulting in memory impairment in adult male mouse offspring.

Exposure to toxic elements in drinking water, such as arsenic (As) and fluoride (F), starts at gestation and has been associated with memory and learning deficits in children. Studies in which rodents underwent mechanistic single exposure to As or F showed that the neurotoxic effects are associated with their capacity to disrupt redox balance, mainly by diminishing glutathione (GSH) levels, altering glutamate disposal, and altering glutamate receptor expression, which disrupts synaptic transmission. Elevated levels of As and F are common in groundwater worldwide. To explore the neurotoxicity of chronic exposure to As and F in drinking water, pregnant CD-1 mice were exposed to 2 mg/L As (sodium arsenite) and 25 mg/L F (sodium fluoride) alone or in combination. The male litter continued to receive exposure up to 30 or 90 days after birth. The effects of chronic exposure on GSH levels, transsulfuration pathway enzymatic activity, expression of cysteine/cystine transporters, glutamate transporters, and ionotropic glutamate receptor subunits as well as behavioral performance in the object recognition memory task were assessed. Combined exposure resulted in a significant reduction in GSH levels in the cortex and hippocampus at different times, decreased transsulfuration pathway enzyme activity, as well as diminished xCT protein expression. Altered glutamate receptor expression in the cortex and hippocampus and decreased transaminase enzyme activity were observed. These molecular alterations were associated with memory impairment in the object recognition task, which relies on these brain regions.

Transoral removal of submandibular hilar lithiasis: results on the salivary duct system, glandular parenchyma, and quality-of-life recovery.

OBJECTIVE(S): To confirm that hilar transoral submandibular sialolitectomy (TOSL) is the first treatment option for submandibular hilar lithiasis (SHL) in terms of glandular parenchyma recovery, salivary system restoration, and patient quality of life (QoL) improvement. METHODS: Depending on whether the stone was easily palpable, TOSL was carried out with or without sialendoscopy. For the first time in the literature, Magnetic Resonance Sialography (MR-Si) was performed before and after TOSL, to evaluate stone characteristics, glandular parenchyma status, hilum dilation and main duct recanalization. Radiological data was examined independently by two radiologists. COSQ, a recently validated and specific questionnaire, was used to assess associated QoL. RESULTS: Between 2017 and 2022, 29 TOSL patients were examined. With a high interobserver correlation, MR-Si was confirmed as a very useful radiological test in the pre- and post-surgical evaluation of SHL. The salivary main duct was completely recanalized in all cases. The presence of lithiasis was found in 4 patients (13.8%). After surgery, the majority of patients (79.31%) had hilum dilation. There was a statistically significant improvement in parenchyma status, but no significant progression to glandular atrophy. After surgery, COSQ mean values always improved (22.5 to 4.5). CONCLUSIONS: TOSL is the ideal surgical technique for the management of SHL, resulting in improved parenchymal inflammatory changes, recanalization of Wharton's duct, and enhancement patients' QoL. As a result, before removing the submandibular gland, TOSL should be considered as the first treatment option for SHL.

Modified lanthanide-doped carbon dots as a novel nanochemosensor for efficient detection of water in toluene and its potential application in lubricant base oils.

A fast and efficient method was developed for obtaining europium(III)-doped surface-modified carbon dots with a hydrophobic coating. This surface functionalization improved the dispersibility of the nanoparticles in non-polar media, as well as modified the accessibility of water molecules to the europium ions. These two features allowed studying the application of doped carbon dots as moisture nanochemosensor, demonstrating high stability over time of both the photoluminescent signal intensity and the stability of the dispersions. The developed nanochemosensor was used to determine water in toluene with a detection limit of 8.5 × 10-4 M and a quantification limit of 2.4 × 10-3 M. The proposed system matches and even improves other methodologies for water determination in organic solvents; it has a low detection limit and a fast response time (almost instantaneous) and requires neither expensive material nor trained personnel. The results suggest a promising future for the development of a new sensing phase for moisture determination in lubricant base oil.

A Low-Cost Hardware Architecture for EV Battery Cell Characterization Using an IoT-Based Platform.

Since 1997, when the first hybrid vehicle was launched on the market, until today, the number of NIMH batteries that have been discarded due to their obsolescence has not stopped increasing, with an even faster rate more recently due to the progressive disappearance of thermal vehicles on the market. The battery technologies used are mostly NIMH for hybrid vehicles and Li ion for pure electric vehicles, making recycling difficult due to the hazardous materials they contain. For this reason, and with the aim of extending the life of the batteries, even including a second life within electric vehicle applications, this paper describes and evaluates a low-cost system to characterize individual cells of commercial electric vehicle batteries by identifying such abnormally performing cells that are out of use, minimizing regeneration costs in a more sustainable manner. A platform based on the IoT technology is developed, allowing the automation of charging and discharging cycles of each independent cell according to some parameters given by the user, and monitoring the real-time data of such battery cells. A case study based on a commercial Toyota Prius battery is also included in the paper. The results show the suitability of the proposed solution as an alternative way to characterize individual cells for subsequent electric vehicle applications, decreasing operating costs and providing an autonomous, flexible, and reliable system.

BDNF and Cognitive Function in Chilean Schizophrenic Patients.

Despite cognitive symptoms being very important in schizophrenia, not every schizophrenic patient has a significant cognitive deficit. The molecular mechanisms underlying the different degrees of cognitive functioning in schizophrenic patients are not sufficiently understood. We studied the relation between brain-derived neurotrophic factor (BDNF) and cognitive functioning in two groups of schizophrenic patients with different cognitive statuses. According to the Montreal Cognitive Assessment (MoCA) results, the schizophrenic patients were classified into two subgroups: normal cognition (26 or more) and cognitive deficit (25 or less). We measured their plasma BDNF levels using ELISAs. The statistical analyses were performed using Spearman's Rho and Kruskal-Wallis tests. We found a statistically significant positive correlation between the plasma BDNF levels and MoCA score (p = 0.04) in the subgroup of schizophrenic patients with a cognitive deficit (n = 29). However, this correlation was not observed in the patients with normal cognition (n = 11) and was not observed in the total patient group (n = 40). These results support a significant role for BDNF in the cognitive functioning of schizophrenics with some degree of cognitive deficit, but suggest that BDNF may not be crucial in patients with a normal cognitive status. These findings provide information about the molecular basis underlying cognitive deficits in this illness.

Drug repurposing for cancer therapy, easier said than done.

Drug repurposing for cancer therapy is currently a hot topic of research. Theoretically, in contrast to the known hurdles of developing new molecular entities, the approach of repurposing has several advantages. Mostly, it is said that it is faster, safer, easier, and cheaper. In the real world, however, there are only three repurposed drugs so far, that are listed in widely recognized cancer guidelines, but a large number of them are being studied. Among the many barriers to repurposing cancer drugs, economical-driven are the most important that difficult the clinical development of them. In this review, we provide an overview of the current status of drug repurposing for cancer therapy and the barriers that need to be overcome to realize the benefit of this approach. It means to have repositioned drugs for cancer therapy accepted as standard therapy for cancer indications at low cost.

Progress in the mechanism of neuronal surface P antigen modulating hippocampal function and implications for autoimmune brain disease.

PURPOSE OF REVIEW: The aim of this study was to present a new regulation system in the hippocampus constituted by the neuronal surface P antigen (NSPA) and the tyrosine phosphatase PTPMEG/PTPN4, which provides mechanistic and therapeutic possibilities for cognitive dysfunction driven by antiribosomal P protein autoantibodies in patients with systemic lupus erythematosus (SLE). RECENT FINDINGS: Mice models lacking the function of NSPA as an E3 ubiquitin ligase show impaired glutamatergic synaptic plasticity, decreased levels of NMDAR at the postsynaptic density in hippocampus and memory deficits. The levels of PTPMEG/PTPN4 are increased due to lower ubiquitination and proteasomal degradation, resulting in dephosphorylation of tyrosines that control endocytosis in GluN2 NMDAR subunits. Adult hippocampal neurogenesis (AHN) that normally contributes to memory processes is also defective in the absence of NSPA. SUMMARY: NSPA function is crucial in memory processes controlling the stability of NMDAR at PSD through the ubiquitination of PTPMEG/PTPN4 and also through AHN. As anti-P autoantibodies reproduce the impairments of glutamatergic transmission, plasticity and memory performance seen in the absence of NSPA, it might be expected to perturb the NSPA/PTPMEG/PTPN4 pathway leading to hypofunction of NMDAR. This neuropathogenic mechanism contrasts with that of anti-NMDAR antibodies also involved in lupus cognitive dysfunction. Testing this hypothesis might open new therapeutic possibilities for cognitive dysfunction in SLE patients bearing anti-P autoantibodies.

Democratization of PV Micro-Generation System Monitoring Based on Narrowband-IoT.

Power system configuration and performance are changing very quickly. Under the new paradigm of prosumers and energy communities, grids are increasingly influenced by microgeneration systems connected in both low and medium voltage. In addition, these facilities provide little or no information to distribution and/or transmission system operators, increasing power system management problems. Actually, information is a great asset to manage this new situation. The arrival of affordable and open Internet of Things (IoT) technologies is a remarkable opportunity to overcome these inconveniences allowing for the exchange of information about these plants. In this paper, we propose a monitoring solution applicable to photovoltaic self-consumption or any other microgeneration installation, covering the installations of the so-called 'prosumers' and aiming to provide a tool for local self-consumption monitoring. A detailed description of the proposed system at the hardware level is provided, and extended information on the communication characteristics and data packets is also included. Results of different field test campaigns carried out in real PV self-consumption installations connected to the grid are described and analyzed. It can be affirmed that the proposed solution provides outstanding results in reliability and accuracy, being a popular solution for those who cannot afford professional monitoring platforms.

Design and Characterization of In-One Protease-Esterase PluriZyme.

Proteases are abundant in prokaryotic genomes (~10 per genome), but their recovery encounters expression problems, as only 1% can be produced at high levels; this value differs from that of similarly abundant esterases (1-15 per genome), 50% of which can be expressed at good levels. Here, we design a catalytically efficient artificial protease that can be easily produced. The PluriZyme EH1AB1 with two active sites supporting the esterase activity was employed. A Leu24Cys mutation in EH1AB1, remodelled one of the esterase sites into a proteolytic one through the incorporation of a catalytic dyad (Cys24 and His214). The resulting artificial enzyme, EH1AB1C, efficiently hydrolysed (azo)casein at pH 6.5-8.0 and 60-70 °C. The presence of both esterase and protease activities in the same scaffold allowed the one-pot cascade synthesis (55.0 ± 0.6% conversion, 24 h) of L-histidine methyl ester from the dipeptide L-carnosine in the presence of methanol. This study demonstrates that active sites supporting proteolytic activity can be artificially introduced into an esterase scaffold to design easy-to-produce in-one protease-esterase PluriZymes for cascade reactions, namely, the synthesis of amino acid esters from dipeptides. It is also possible to design artificial proteases with good production yields, in contrast to natural proteases that are difficult to express.

Can we predict an incomplete capsule endoscopy? Results of a multivariate analysis using a logistic regression model.

BACKGROUND AND AIMS: small bowel capsule endoscopy (SBCE) does not reach the cecum within the battery lifetime in approximately 15-35 % of patients. Incomplete examinations result in diagnostic delays and increase the economic burden. To date, risk factors for incomplete examinations have been described with contradictory results. The aims of this study were to analyze the rate and identify risk factors for incomplete examinations, excluding capsule retentions, in a large cohort of patients. METHODS: data from 1,894 consecutive SBCE examinations performed from January 2009 to December 2015 were analyzed. Variables recorded included demographics, past medical and surgical history, biochemical parameters and procedure characteristics. The rate of incomplete examinations, excluding capsule retentions, was calculated and a multivariate analysis using a logistic regression model was performed in order to evaluate predictive factors. RESULTS: the incidence of incomplete examinations, excluding capsule retentions, was 10.1 % (187 incomplete procedures). The multivariate analysis showed that age > 65 years, gastric transit time > 41 minutes and SB transit time > 286 minutes are predictive factors for incomplete examinations, increasing the probability of this event by 199 % (OR: 1.99; 95 % CI: 1.34-2.95), 260 % (OR: 2.60; 95 % CI: 1.72-3.93) and 352 % (OR: 3.52; 95 % CI: 2.26-5.48), respectively. CONCLUSIONS: age > 65 years, gastric transit time > 41 minutes and SB transit time > 286 minutes are predictive factors for incomplete examinations excluding capsule retentions. Both age and gastric transit time events are known before the procedure ends. Therefore, pharmacologic or endoscopic measures may be taken into account to avoid incomplete examinations.

A Plurizyme with Transaminase and Hydrolase Activity Catalyzes Cascade Reactions.

Engineering dual-function single polypeptide catalysts with two abiotic or biotic catalytic entities (or combinations of both) supporting cascade reactions is becoming an important area of enzyme engineering and catalysis. Herein we present the development of a PluriZyme, TR2 E2 , with efficient native transaminase (kcat : 69.49±1.77 min-1 ) and artificial esterase (kcat : 3908-0.41 min-1 ) activities integrated into a single scaffold, and evaluate its utility in a cascade reaction. TR2 E2 (pHopt : 8.0-9.5; Topt : 60-65 °C) efficiently converts methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate into 3-(R)-amino-4-(2,4,5-trifluorophenyl)butanoic acid, a crucial intermediate for the synthesis of antidiabetic drugs. The reaction proceeds through the conversion of the ß-keto ester into the ß-keto acid at the hydrolytic site and subsequently into the ß-amino acid (e.e. >99 %) at the transaminase site. The catalytic power of the TR2 E2 PluriZyme was proven with a set of ß-keto esters, demonstrating the potential of such designs to address bioinspired cascade reactions.

Prognostic factors associated with unhealed perineal wounds post-proctectomy for perianal Crohn's disease: a two-centre study.

AIM: The aim of this work was to determine the factors associated with poor wound healing in patients with perianal Crohn's disease (pCD) who had undergone proctectomy in the era of biologic therapies. METHOD: Case record review was performed on 103 patients with pCD who underwent proctectomy at St Mark's Hospital, Harrow and the Western General Hospital, Edinburgh between 2005 and 2017. Healing rates at 6 and 12 months post-proctectomy were considered; univariate analysis was performed. RESULTS: Sixty out of 103 patients (58.3%) had failure of wound healing at 6 months and 41/103 (39.8%) at 12 months. In total, 63.1% (65/103) patients received biologic therapies prior to proctectomy; however, exposure to biologics was not a significant factor in predicting failure of wound healing at 12 months (infliximab p = 0.255; adalimumab p = 0.889; vedolizumab p = 0.153). Male gender was the only variable associated with poor wound healing at 12 months on univariate analysis (p = 0.017). A lower pre-operative C-reactive protein was associated with early wound healing at 6 months compared with at 12 months (p = 0.041) on univariate analysis. Other parameters not associated with rates of wound healing included smoking status, corticosteroid exposure, thiopurine exposure, number of previous biologics, perianal sepsis on MRI within the last 12 months, duration of CD prior to proctectomy and pre-operative albumin. CONCLUSION: More than a third of patients had unhealed wounds 12 months after proctectomy. We report that unhealed wounds are more common in male patients. Importantly, our results also suggest that exposure to biologics does not affect rates of wound healing.

Wind from the black-hole accretion disk driving a molecular outflow in an active galaxy.

Powerful winds driven by active galactic nuclei are often thought to affect the evolution of both supermassive black holes and their host galaxies, quenching star formation and explaining the close relationship between black holes and galaxies. Recent observations of large-scale molecular outflows in ultraluminous infrared galaxies support this quasar-feedback idea, because they directly trace the gas from which stars form. Theoretical models suggest that these outflows originate as energy-conserving flows driven by fast accretion-disk winds. Proposed connections between large-scale molecular outflows and accretion-disk activity in ultraluminous galaxies were incomplete because no accretion-disk wind had been detected. Conversely, studies of powerful accretion-disk winds have until now focused only on X-ray observations of local Seyfert galaxies and a few higher-redshift quasars. Here we report observations of a powerful accretion-disk wind with a mildly relativistic velocity (a quarter that of light) in the X-ray spectrum of IRAS F11119+3257, a nearby (redshift 0.189) optically classified type 1 ultraluminous infrared galaxy hosting a powerful molecular outflow. The active galactic nucleus is responsible for about 80 per cent of the emission, with a quasar-like luminosity of 1.5 × 10(46) ergs per second. The energetics of these two types of wide-angle outflows is consistent with the energy-conserving mechanism that is the basis of the quasar feedback in active galactic nuclei that lack powerful radio jets (such jets are an alternative way to drive molecular outflows).

A live porcine model for surgical training in tracheostomy, neck dissection, and total laryngectomy.

OBJECTIVES: Head and neck surgery is associated with a steep learning curve, creating a need for effective training methods. Live animal models can be useful in acquiring the required skills and techniques to perform tracheostomy, neck dissection, and laryngectomy. The aim of this study is to assess the feasibility and usefulness of a porcine model to teach tracheostomy, neck dissection, and laryngectomy, describing the similarities between a swine head and neck surgical model and the human cervical area. METHODS: Twelve surgical training sessions were held with the use of a live porcine model maintained under general anaesthesia; a total of 39 procedures were performed. In each session, one otolaryngology resident per year performed a procedure to acquire the targeted competencies for their respective year of training. Each procedure was time recorded and evaluated based on a modified Objective Structured Assessment of Technical Skills. Linear regression was used to analyse the data and express the results as percentages. RESULTS: Training exercises were performed in shorter times over the study period. A 9% reduction in the time spent was observed. There was a global improvement in the evaluation made by OSATS score of 6% in the first period (2018-2019) and 58% in the second period (2019-2020). CONCLUSION: The porcine model was both manageable and helpful in providing training despite slight anatomical differences between human beings and pigs. However, more studies are necessary to guarantee that the competencies acquired with this type of training are transferable to real-life interventions. LEVEL OF EVIDENCE: Level 5.

Neuronal surface P antigen (NSPA) modulates postsynaptic NMDAR stability through ubiquitination of tyrosine phosphatase PTPMEG.

BACKGROUND: Cognitive dysfunction (CD) is common among patients with the autoimmune disease systemic lupus erythematosus (SLE). Anti-ribosomal P autoantibodies associate with this dysfunction and have neuropathogenic effects that are mediated by cross-reacting with neuronal surface P antigen (NSPA) protein. Elucidating the function of NSPA can then reveal CD pathogenic mechanisms and treatment opportunities. In the brain, NSPA somehow contributes to glutamatergic NMDA receptor (NMDAR) activity in synaptic plasticity and memory. Here we analyze the consequences of NSPA absence in KO mice considering its structural features shared with E3 ubiquitin ligases and the crucial role of ubiquitination in synaptic plasticity. RESULTS: Electrophysiological studies revealed a decreased long-term potentiation in CA3-CA1 and medial perforant pathway-dentate gyrus (MPP-DG) hippocampal circuits, reflecting glutamatergic synaptic plasticity impairment in NSPA-KO mice. The hippocampal dentate gyrus of these mice showed a lower number of Arc-positive cells indicative of decreased synaptic activity and also showed proliferation defects of neural progenitors underlying less adult neurogenesis. All this translates into poor spatial and recognition memory when NSPA is absent. A cell-based assay demonstrated ubiquitination of NSPA as a property of RBR-type E3 ligases, while biochemical analysis of synaptic regions disclosed the tyrosine phosphatase PTPMEG as a potential substrate. Mice lacking NSPA have increased levels of PTPMEG due to its reduced ubiquitination and proteasomal degradation, which correlated with lower levels of GluN2A and GluN2B NMDAR subunits only at postsynaptic densities (PSDs), indicating selective trafficking of these proteins out of PSDs. As both GluN2A and GluN2B interact with PTPMEG, tyrosine (Tyr) dephosphorylation likely drives their endocytic removal from the PSD. Actually, immunoblot analysis showed reduced phosphorylation of the GluN2B endocytic signal Tyr1472 in NSPA-KO mice. CONCLUSIONS: NSPA contributes to hippocampal plasticity and memory processes ensuring appropriate levels of adult neurogenesis and PSD-located NMDAR. PTPMEG qualifies as NSPA ubiquitination substrate that regulates Tyr phosphorylation-dependent NMDAR stability at PSDs. The NSPA/PTPMEG pathway emerges as a new regulator of glutamatergic transmission and plasticity and may provide mechanistic clues and therapeutic opportunities for anti-P-mediated pathogenicity in SLE, a still unmet need.