Humoral pathways of innate immune regulation in granuloma formation.

The humoral arm of mammalian innate immunity regulates several molecular mechanisms involved in resistance to pathogens, inflammation, and tissue repair. Recent studies highlight the crucial role played by humoral mediators in granulomatous inflammation. However the molecular mechanisms linking the function of these soluble molecules to the initiation and maintenance of granulomas remain elusive. We propose that humoral innate immunity coordinates fundamental physiological processes in macrophages which, in turn, initiate activation and transformation events that enable granuloma formation. We discuss the involvement of humoral mediators in processes such as immune activation, phagocytosis, metabolism, and tissue remodeling, and how these can dictate macrophage functionality during granuloma formation. These advances present opportunities for discovering novel disease factors and developing targeted, more effective treatments for granulomatous diseases.

Twelve-year trends in unprotected left main coronary artery occlusion: insights from a real-world multicentre study.

AIMS: Acute myocardial infarction (AMI) resulting from unprotected left main coronary artery (LMCA) occlusion and subtotal occlusion is a life-threatening condition. Although AMI management has improved in the past two decades, there is limited information on recent trends in patient characteristics, management, and outcomes for acute unprotected LMCA-related AMI. This study aims to assess such trends over a 12 year period. METHODS AND RESULTS: This retrospective multicentre study includes patients with unprotected LMCA occlusion/subtotal occlusion admitted to three tertiary hospitals between 2008 and 2020. The patients were divided into two groups based on the chronology of presentation: a 'past group' (January 2008 to December 2014) and a 'contemporary group' (January 2015 to December 2020). The study compares clinical characteristics, management approaches, and outcomes between the two groups. The study includes 128 patients, with 51 (40%) in the 'past group' and 77 (60%) in the 'contemporary group'. Baseline risk factors did not show statistically significant differences between the two groups, except for hypertension (49% vs. 74%; P = 0.005). Chest pain was more frequent in the 'past group' (98% vs. 89%; P = 0.014), and a trend towards more cardiac arrests was observed in the 'contemporary group' (18% vs. 31%; P = 0.087). Revascularization type did not differ significantly (P = 0.419), but manual thrombectomy was less frequently used (41% vs. 23%; P = 0.032) and stent implantation showed a trend towards higher rates (66% vs. 78%; P = 0.150) in the 'contemporary cohort'. There was a gradual shift from bare-metal to drug-eluting stents, with a significantly higher percentage of ticagrelor/prasugrel loading in the 'contemporary cohort' (5% vs. 79%; P < 0.001). The use of mechanical circulatory support (MCS), although not statistically significant, was higher among patients in the 'past group' (67% vs. 51%; P = 0.073). The type of MCS differed significantly between groups, with a decrease in intra-aortic balloon pump use (67% vs. 42%; P = 0.005) and an increase in veno-arterial extracorporeal membrane oxygenation (4% vs. 22%; P = 0.005) and Impella system (0% vs. 3%) over time. Survival analysis showed no significant differences (P = 0.599; log-rank test) in all-cause mortality between the different time groups, with the long-term survival rate being approximately 30%. CONCLUSIONS: In our real-world population, despite the progressive use of newer drugs and more advanced devices over time, patients with unprotected LMCA occlusion/subtotal occlusion remain a subpopulation with poor prognosis.

Fatal cervical myelopathy in a child with glutaric aciduria type 1.

We report the case of a Syrian female refugee with late diagnosis of glutaric aciduria type 1 characterised by massive axial hypotonia and quadriplegia who only started adequate diet upon arrival in Switzerland at the age of 4 years, after a strenuous migration journey. Soon after arrival, she died from an unexpected severe upper cervical myelopathy, heralded by acute respiratory distress after a viral infection. This was likely due to repeated strains on her hypotonic neck and precipitated by an orthotopic os odontoideum who led to atlanto-axial subluxation. This case reminds us not to omit handling patients with insufficient postural control and hypotonia with great care to avoid progressive cervical myelopathy.

Influenza A virus propagation requires the activation of the unfolded protein response and the accumulation of insoluble protein aggregates.

Influenza A virus (IAV) employs multiple strategies to manipulate cellular mechanisms and support proper virion formation and propagation. In this study, we performed a detailed analysis of the interplay between IAV and the host cells' proteostasis throughout the entire infectious cycle. We reveal that IAV infection activates the inositol requiring enzyme 1 (IRE1) branch of the unfolded protein response, and that this activation is important for an efficient infection. We further observed the accumulation of virus-induced insoluble protein aggregates, containing both viral and host proteins, associated with a dysregulation of the host cell RNA metabolism. Our data indicate that this accumulation is important for IAV propagation and favors the final steps of the infection cycle, more specifically the virion assembly. These findings reveal additional mechanisms by which IAV disrupts host proteostasis and uncovers new cellular targets that can be explored for the development of host-directed antiviral strategies.

ST-Segment Elevation: An Unexpected Culprit.

The clinical presentation of pulmonary embolism (PE) and acute coronary syndrome can be similar. We report a case of a patient presenting with antero-septal ST-segment elevation after cardiac arrest, found to have acute-PE-mimicking ST-segment elevation myocardial infarction (STEMI), treated with aspiration thrombectomy and catheter-directed thrombolysis (CDT). A 78-year-old man was admitted with dyspnea, chest pain and tachycardia. During evaluation, cardiac arrest in pulseless electrical activity was documented. Advanced life support was started immediately. ECG post-ROSC revealed ST-segment elevation in V1-V4 and aVR. Echocardiography showed normal left ventricular function but right ventricular (RV) dilation and severe dysfunction. The patient was in shock and was promptly referred to cardiac catheterization that excluded significant CAD. Due to the discordant ECG and echocardiogram findings, acute PE was suspected, and immediate invasive pulmonary angiography revealed bilateral massive pulmonary embolism. Successful aspiration thrombectomy was performed followed by local alteplase infusion. At the end of the procedure, mPAP was reduced and blood pressure normalized allowing withdrawal of vasopressor support. Twenty-four-hour echocardiographic reassessment showed normal-sized cardiac chambers with preserved biventricular systolic function. Bedside echocardiography in patients with ST-segment elevation post-ROSC is instrumental in raising the suspicion of acute PE. In the absence of a culprit coronary lesion, prompt pulmonary angiography should be considered if immediately feasible. In these cases, CDT and aspiration in high-risk acute PE seem safe and effective in relieving obstructive shock and restoring hemodynamics.

The hidden RNA code: implications of the RNA epitranscriptome in the context of viral infections.

Emerging evidence highlights the multifaceted roles of the RNA epitranscriptome during viral infections. By modulating the modification landscape of viral and host RNAs, viruses enhance their propagation and elude host surveillance mechanisms. Here, we discuss how specific RNA modifications, in either host or viral RNA molecules, impact the virus-life cycle and host antiviral responses, highlighting the potential of targeting the RNA epitranscriptome for novel antiviral therapies.

Bleomycin-induced lung injury: Revisiting an old tool to model group III PH associated with pulmonary fibrosis.

Pulmonary hypertension (PH) is a chronic disorder of the pulmonary circulation that often associates with other respiratory diseases (i.e., group III PH), leading to worsened symptoms and prognosis, notably when combined with interstitial lung diseases such as pulmonary fibrosis (PF). PH may lead to right ventricular (RV) failure, which accounts for a substantial part of the mortality in chronic lung disease patients. The disappointing results of pulmonary arterial hypertension (PAH)-related therapies in patients with PF emphasize the need to better understand the pathophysiologic mechanisms that drive PH development and progression in this specific setting. In this work, we validated an animal model of group III PH associated with PF (PH-PF), by using bleomycin (BM) intratracheal instillation and characterizing the nature of induced lung and vascular remodeling, including the influence on RV structure and function. To our knowledge, this is the first work describing this dose of BM in Sprague Dawley rats and the effects upon the heart and lungs, using different techniques such as echocardiography, heart catheterization, and histology. Our data shows the successful implementation of a rat model that mimics combined PF-PH, with most features seen in the equivalent human disease, such as lung and arterial remodeling, increased mPAP and RV dysfunction.

The structure of a Bacteroides thetaiotaomicron carbohydrate-binding module provides new insight into the recognition of complex pectic polysaccharides by the human microbiome.

The Bacteroides thetaiotaomicron has developed a consortium of enzymes capable of overcoming steric constraints and degrading, in a sequential manner, the complex rhamnogalacturonan II (RG-II) polysaccharide. BT0996 protein acts in the initial stages of the RG-II depolymerisation, where its two catalytic modules remove the terminal monosaccharides from RG-II side chains A and B. BT0996 is modular and has three putative carbohydrate-binding modules (CBMs) for which the roles in the RG-II degradation are unknown. Here, we present the characterisation of the module at the C-terminal domain, which we designated BT0996-C. The high-resolution structure obtained by X-ray crystallography reveals that the protein displays a typical ß-sandwich fold with structural similarity to CBMs assigned to families 6 and 35. The distinctive features are: 1) the presence of several charged residues at the BT0996-C surface creating a large, broad positive lysine-rich patch that encompasses the putative binding site; and 2) the absence of the highly conserved binding-site signatures observed in CBMs from families 6 and 35, such as region A tryptophan and region C asparagine. These findings hint at a binding mode of BT0996-C not yet observed in its homologues. In line with this, carbohydrate microarrays and microscale thermophoresis show the ability of BT0996-C to bind α1-4-linked polygalacturonic acid, and that electrostatic interactions are essential for the recognition of the anionic polysaccharide. The results support the hypothesis that BT0996-C may have evolved to potentiate the action of BT0996 catalytic modules on the complex structure of RG-II by binding to the polygalacturonic acid backbone sequence.

Disruption of GCN2 Pathway Aggravates Vascular and Parenchymal Remodeling during Pulmonary Fibrosis.

Pulmonary fibrosis (PF) and pulmonary hypertension (PH) are chronic diseases of the pulmonary parenchyma and circulation, respectively, which may coexist, but underlying mechanisms remain elusive. Mutations in the GCN2 (general control nonderepressible 2) gene (EIF2AK4 [eukaryotic translation initiation factor 2 alpha kinase 4]) were recently associated with pulmonary veno-occlusive disease. The aim of this study is to explore the involvement of the GCN2/eIF2α (eukaryotic initiation factor 2α) pathway in the development of PH during PF, in both human disease and in a laboratory animal model. Lung tissue from patients with PF with or without PH was collected at the time of lung transplantation, and control tissue was obtained from tumor resection surgery. Experimental lung disease was induced in either male wild-type or EIF2AK4-mutated Sprague-Dawley rats, randomly receiving a single intratracheal instillation of bleomycin or saline. Hemodynamic studies and organ collection were performed 3 weeks after instillation. Only significant results (P < 0.05) are presented. In PF lung tissue, GCN2 protein expression was decreased compared with control tissue. GCN2 expression was reduced in CD31+ endothelial cells. In line with human data, GCN2 protein expression was decreased in the lung of bleomycin rats compared with saline. EIF2AK4-mutated rats treated with bleomycin showed increased parenchymal fibrosis (hydroxyproline concentrations) and vascular remodeling (media wall thickness) as well as increased right ventricular systolic pressure compared with wild-type animals. Our data show that GCN2 is dysregulated in both humans and in an animal model of combined PF and PH. The possibility of a causative implication of GCN2 dysregulation in PF and/or PH development should be further studied.

Scaling-Up an Aqueous Self-Degassing Electrochemically Mediated ATRP in Dispersion for the Preparation of Cellulose-Polymer Composites and Films.

Electrochemically mediated atom transfer radical polymerization (eATRP) is developed in dispersion conditions to assist the preparation of cellulose-based films. Self-degassing conditions are achieved by the addition of sodium pyruvate (SP) as a ROS scavenger, while an aluminum counter electrode provides a simplified and more cost-effective electrochemical setup. Different polyacrylamides were grown on a model cellulose substrate which was previously esterified with 2-bromoisobutyrate (-BriB), serving as initiator groups. Small-scale polymerizations (15 mL) provided optimized conditions to pursue the scale-up up to 1000 mL (scale-up factor ~67). Cellulose-poly(N-isopropylacrylamide) was then chosen to prepare the tunable, thermoresponsive, solvent-free, and flexible films through a dissolution/regeneration method. The produced films were characterized by Fourier-transform infrared (FTIR), scanning electron microscopy (SEM), dynamic scanning calorimetry (DSC), and thermogravimetric analysis (TGA).

Guided Endodontics: Static vs. Dynamic Computer-Aided Techniques-A Literature Review.

(1) Background: access cavity preparation is the first stage of non-surgical endodontic treatment. The inaccuracy of this step may lead to numerous intraoperative complications, which impair the root canal treatment's prognosis and therefore the tooth's survival. Guided endodontics, meaning computer-aided static (SN) and dynamic navigation (DN) techniques, has recently emerged as a new approach for root canal location in complex cases. This review aims to compare SN and DN guided endodontics' techniques in non-surgical endodontic treatment. (2) Methods: an electronic search was performed on PubMed, Scopus, and Cochrane Library databases until October 2021. Studies were restricted by language (English, Spanish and Portuguese) and year of publication (from 2011 to 2021). (3) Results: a total of 449, 168 and 32 articles were identified in PubMed, Scopus, and Cochrane Library databases, respectively, after the initial search. Of the 649 articles, 134 duplicates were discarded. In this case, 67 articles were selected after title and abstract screening, of which 60 were assessed for eligibility through full-text analysis, with one article being excluded. Four cross-references were added. Thus, 63 studies were included. (4) Conclusions: guided endodontics procedures present minimally invasive and accurate techniques which allow for highly predictable root canal location, greater tooth structure preservation and lower risk of iatrogenic damage, mainly when performed by less experienced operators. Both SN and DN approaches exhibit different advantages and disadvantages that make them useful in distinct clinical scenarios.

Process Development for Flexible Films of Industrial Cellulose Pulp Using Superbase Ionic Liquids.

Due to environmental concerns, more attention has been given to the development of bio-based materials for substitution of fossil-based ones. Moreover, paper use is essential in daily routine and several applications of industrial pulp can be developed. In this study, transparent films were produced by industrial cellulose pulp solubilization in tetramethylguanidine based ionic liquids followed by its regeneration. Films were characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), UV/Vis spectroscopy, proton nuclear magnetic resonance (1H-NMR), dynamic scanning calorimetry (DSC), thermal analysis (TG), and X-ray diffraction (XRD). Mechanical tests showed that films have a good elongation property, up to 50%, depending on ionic liquid incorporation. The influence of the conjugated acid and dissolution temperature on mechanical properties were evaluated. These results revealed the potential of this methodology for the preparation of new biobased films.

m5U54 tRNA Hypomodification by Lack of TRMT2A Drives the Generation of tRNA-Derived Small RNAs.

Transfer RNA (tRNA) molecules contain various post-transcriptional modifications that are crucial for tRNA stability, translation efficiency, and fidelity. Besides their canonical roles in translation, tRNAs also originate tRNA-derived small RNAs (tsRNAs), a class of small non-coding RNAs with regulatory functions ranging from translation regulation to gene expression control and cellular stress response. Recent evidence indicates that tsRNAs are also modified, however, the impact of tRNA epitranscriptome deregulation on tsRNAs generation is only now beginning to be uncovered. The 5-methyluridine (m5U) modification at position 54 of cytosolic tRNAs is one of the most common and conserved tRNA modifications among species. The tRNA methyltransferase TRMT2A catalyzes this modification, but its biological role remains mostly unexplored. Here, we show that TRMT2A knockdown in human cells induces m5U54 tRNA hypomodification and tsRNA formation. More specifically, m5U54 hypomodification is followed by overexpression of the ribonuclease angiogenin (ANG) that cleaves tRNAs near the anticodon, resulting in accumulation of 5'tRNA-derived stress-induced RNAs (5'tiRNAs), namely 5'tiRNA-GlyGCC and 5'tiRNA-GluCTC, among others. Additionally, transcriptomic analysis confirms that down-regulation of TRMT2A and consequently m5U54 hypomodification impacts the cellular stress response and RNA stability, which is often correlated with tiRNA generation. Accordingly, exposure to oxidative stress conditions induces TRMT2A down-regulation and tiRNA formation in mammalian cells. These results establish a link between tRNA hypomethylation and ANG-dependent tsRNAs formation and unravel m5U54 as a tRNA cleavage protective mark.

Iron Deficiency in Pulmonary Arterial Hypertension: A Deep Dive into the Mechanisms.

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease that is caused by the progressive occlusion of the distal pulmonary arteries, eventually leading to right heart failure and death. Almost 40% of patients with PAH are iron deficient. Although widely studied, the mechanisms linking between PAH and iron deficiency remain unclear. Here we review the mechanisms regulating iron homeostasis and the preclinical and clinical data available on iron deficiency in PAH. Then we discuss the potential implications of iron deficiency on the development and management of PAH.

Emerging Roles of tRNAs in RNA Virus Infections.

Viruses rely on the host cell translation machinery for efficient synthesis of their own proteins. Emerging evidence highlights different roles for host transfer RNAs (tRNAs) in the process of virus replication. For instance, different RNA viruses manipulate host tRNA pools to favor viral protein translation. Interestingly, specific host tRNAs are used as reverse transcription primers and are packaged into retroviral virions. Recent data also demonstrate the formation of tRNA-derived fragments (tRFs) upon infection to facilitate viral replication. Here, we comprehensively discuss how RNA viruses exploit distinct aspects of the host tRNA biology for their benefit. In light of the recent advances in the field, we propose that host tRNA-related pathways and mechanisms represent promising cellular targets for the development of novel antiviral strategies.

Molecular basis for the preferential recognition of ß1,3-1,4-glucans by the family 11 carbohydrate-binding module from Clostridium thermocellum.

Understanding the specific molecular interactions between proteins and ß1,3-1,4-mixed-linked d-glucans is fundamental to harvest the full biological and biotechnological potential of these carbohydrates and of proteins that specifically recognize them. The family 11 carbohydrate-binding module from Clostridium thermocellum (CtCBM11) is known for its binding preference for ß1,3-1,4-mixed-linked over ß1,4-linked glucans. Despite the growing industrial interest of this protein for the biotransformation of lignocellulosic biomass, the molecular determinants of its ligand specificity are not well defined. In this report, a combined approach of methodologies was used to unravel, at a molecular level, the ligand recognition of CtCBM11. The analysis of the interaction by carbohydrate microarrays and NMR and the crystal structures of CtCBM11 bound to ß1,3-1,4-linked glucose oligosaccharides showed that both the chain length and the position of the ß1,3-linkage are important for recognition, and identified the tetrasaccharide Glcß1,4Glcß1,4Glcß1,3Glc sequence as a minimum epitope required for binding. The structural data, along with site-directed mutagenesis and ITC studies, demonstrated the specificity of CtCBM11 for the twisted conformation of ß1,3-1,4-mixed-linked glucans. This is mediated by a conformation-selection mechanism of the ligand in the binding cleft through CH-π stacking and a hydrogen bonding network, which is dependent not only on ligand chain length, but also on the presence of a ß1,3-linkage at the reducing end and at specific positions along the ß1,4-linked glucan chain. The understanding of the detailed mechanism by which CtCBM11 can distinguish between linear and mixed-linked ß-glucans strengthens its exploitation for the design of new biomolecules with improved capabilities and applications in health and agriculture. DATABASE: Structural data are available in the Protein Data Bank under the accession codes 6R3M and 6R31.

Bloqueio no desenvolvimento emocional: diálogo entre as concepções de couraça e falso self / Bloqueo en el desarrollo emocional: el diálogo entre las concepciones del coraza y falso self / Blockage on emotional development: dialogue between the concepts of armor and false self

Ao longo da literatura psicanalítica, observamos casos em que o analista encontra dificuldade ao lidar com certos tipos de pacientes, estes que apresentam pouca melhora sem um manejo especial. Baseando-se nisso, consideramos que Donald Winnicott e Wilhelm Reich trazem importantes contribuições para o tema, principalmente quando introduzem os conceitos de falso self e couraça. Nosso objetivo, portanto, delineia-se em estabelecer um breve diálogo entre estes conceitos, destacando algumas aproximações e distanciamentos. A metodologia de pesquisa se faz por meio do levantamento bibliográfico, sendo de natureza qualitativa e histórica. Ao final do trabalho, concluímos que os conceitos de couraça e falso self mais se aproximam do que se distanciam, na medida em que dizem respeito ao bloqueio emocional, da motilidade, da agressividade e da espontaneidade (AU).

Throughout the psychoanalytic literature, we observe cases where the analyst finds difficulty to deal with some kind of patients, those who do not present a significant improvement without a special handling. Based on this, we consider that Donald Winnicott and Wilhelm Reich bring important contributions to the theme, especially when they introduce the concepts of false self and armor. Our objective, therefore, is to establish a short dialogue between these concepts, emphasizing some approximations and distinctions. The research methodology is done through a bibliographic survey, being of qualitative and historical nature. At the end of the work, we concluded that the concepts of armor and false self are more similar than they are different in relation to emotional, motility, aggressiveness and spontaneity blockage (AU).

A lo largo de la literatura psicoanalítica, hemos observado casos en los que al analista le resulta difícil trabajar con ciertos tipos de pacientes, estos que tienen poca mejora sin tratamiento especial. En base a esto, creemos que Donald Winnicott y Wilhelm Reich traen importantes contribuciones al tema, principalmente cuando introducen los conceptos de falso self y coraza. Nuestro objetivo, por tanto, se delinea en establecer un breve diálogo entre estos conceptos, destacando algunas aproximaciones y distanciamientos. La metodología de investigación se produce por medio del levantamiento bibliográfico, siendo de naturaleza cualitativa e histórica. Al final del trabajo, nosotros concluimos que los conceptos de coraza y falso self están más cerca que distantes en lo que se refiere al bloqueo emocional, la motilidad, la agresividad y la espontaneidad (AU).

Effect of Sleeve Gastrectomy on Angiogenesis and Adipose Tissue Health in an Obese Animal Model of Type 2 Diabetes.

INTRODUCTION: Metabolic surgery has become an accepted option for the treatment of obesity and associated metabolic diseases like hypertension and type 2 diabetes. Adipose tissue dysfunction and ectopic storage of excess lipids are thought to be involved in the underlying pathophysiological process. OBJECTIVES: The present study aims to clarify the effect of sleeve gastrectomy (SG) on adipose tissue microvasculature and health in an animal model of adipose type 2 diabetes. METHODS: After weaning, diabetic Goto-Kakizaki rats were either fed on standard rat chow or high-calorie diet. At 4 months, animals on high-calorie diet were randomized to SG, sham surgery, or control group. Non-diabetic Wistar rats served as further controls. At 6 months, glucose and lipid metabolisms were studied in vivo. After sacrifice, periepididymal adipose tissue was collected for histology and analysis of parameters of adipose tissue metabolism and insulin sensitivity. RESULTS: SG decreased body and adipose tissue weight and improved glycemic and lipid profiles. Fasting glycemia, area under the curve after intraperitoneal insulin tolerance test, and insulin resistance were decreased in operated animals. SG also reduced circulating triglycerides and cholesterol while increasing serum adiponectin and adipose tissue peroxisome proliferator-activated receptor γ (PPAR-γ) and perilipin A. Additionally, surgery improved adipose tissue vascular function and markedly increased vascular endothelial growth factor, cluster of differentiation 31, and endothelial nitric oxide synthase. CONCLUSIONS: In our obese animal model of type 2 diabetes, SG significantly improved adipose tissue health and angiogenesis while reducing insulin resistance, involving PPAR-γ and markers of sprouting angiogenesis and endothelial function.