Analysis of Receptor-Type Protein Tyrosine Phosphatase Extracellular Regions with Insights from AlphaFold

The receptor-type protein tyrosine phosphatases (RPTPs) are involved in a wide variety of physiological functions which are mediated via their diverse extracellular regions. They play key roles in cell–cell contacts, bind various ligands and are regulated by dimerization and other processes. Depending on the subgroup, they have been described as everything from ‘rigid rods’ to ‘floppy tentacles’. Here, we review current experimental structural knowledge on the extracellular region of RPTPs and draw on AlphaFold structural predictions to provide further insights into structure and function of these cellular signalling molecules, which are often mutated in disease and are recognised as drug targets. In agreement with experimental data, AlphaFold predicted structures for extracellular regions of R1, and R2B subgroup RPTPs have an extended conformation, whereas R2B RPTPs are twisted, reflecting their high flexibility. For the R3 PTPs, AlphaFold predicts that members of this subgroup adopt an extended conformation while others are twisted, and that certain members, such as CD148, have one or more large, disordered loop regions in place of fibronectin type 3 domains suggested by sequence analysis

Heritability of fetal hemoglobin, white cell count, and other clinical traits from a sickle cell disease family cohort

Sickle cell disease (SCD) is the most common monogenic disorder in the world. Notably, there is extensive clinical heterogeneity in SCD that cannot be fully accounted for by known factors, and in particular, the extent to which the phenotypic diversity of SCD can be explained by genetic variation has not been reliably quantified. Here, in a family-based cohort of 449 patients with SCD and 755 relatives, we first show that 5 known modifiers affect 11 adverse outcomes in SCD to varying degrees. We then utilize a restricted maximum likelihood procedure to estimate the heritability of 20 hematologic traits, including fetal hemoglobin (HbF) and white blood cell count (WBC), in the clinically relevant context of inheritance from healthy carriers to SCD patients. We report novel estimations of heritability for HbF at 31.6% (±5.4%) and WBC at 41.2% (±6.8%) in our cohort. Finally, we demonstrate shared genetic bases between HbF, WBC, and other hematologic traits, but surprisingly little overlap between HbF and WBC themselves. In total, our analyses show that HbF and WBC have significant heritable components among individuals with SCD and their relatives, demonstrating the value of using family-based studies to better understand modifiers of SCD

Profil actuel des bactériémies au Service des Maladies Infectieuses : A propos de 216 cas

Résumé Les caractères épidémiologiques, cliniques et bactériologiques des bactériémies varient en fonction du service où l'étude est réalisée. Le but de ce travail est d’étudier les caractères épidémiologiques des bactériémies observées dans un service de Maladies Infectieuses. Nous avons réalisé une étude rétrospective qui a porté sur 216 épisodes bactériémiques observés chez 216 patients hospitalisés dans le service entre janvier 2013 et juin 2014. L'âge moyen de nos malades était de 40 ans, une tare préexistante était présente chez 108patients (50%), dominée par le diabète (12%), HTA (7%), néphropathie (5%), l’infection a VIH a été retrouvé chez 18% des cas. Une porte d'entrée était identifiée chez 140 malades (65%). Les portes d'entrée urinaire et cutanée étaient les plus fréquentes respectivement dans 48 % et 30 % des épisodes bactériémiques. L'origine nosocomiale de la bactériémie était retenue dans 8% des cas. Les germes les plus fréquemment isolés étaient les bacilles à Gram négatif (54%) au premier rang desquels Escherichia coli suivi de Klebsiella pneumoniae. Les cocci à Gram positif étaient à l'origine de 46 % des bactériémies avec prédominance de Staphylococcus aureus. La mortalité globale était de 15% .La mortalité était de 33% pour la bactériémie à Klebsiella pneumoniae

Stapling and Section of the Nasogastric Tube during Sleeve Gastrectomy: How to Prevent and Recover?

Bariatric surgery has become an integral part of morbid obesity treatment with well-defined indications. Some complications, specific or not, due to laparoscopic sleeve gastrectomy (LSG) procedure have recently been described. We report a rare complication unpublished to date: a nasogastric section during great gastric curve stapling. A 44-year-old woman suffered of severe obesity (BMI 36.6 kg/m2) with failure of medical treatments for years. According to already published technique, a LSG was performed. Six hours postoperatively, a nurse removed the nasogastric tube according to the local protocol and the nasogastric tube was abnormally short, with staples at its extremity. Surgery was performed with peroperative endoscopy. In conclusion, this is the first publication of a nasogastric section during LSG. Therefore we report this case and propose a solution to prevent its occurrence. To avoid this kind of accident, we now systematically insert the nasogastric tube by mouth through a Guedel cannula. Then, to insert the calibrating bougie, we entirely withdraw the nasogastric tube

Hyaluronic acid hydrogels reinforced with laser spun bioactive glass micro- and nanofibres doped with lithium

The repair of articular cartilage lesions in weight-bearing joints remains as a significant challenge due to the low regenerative capacity of this tissue. Hydrogels are candidates to repair lesions as they have similar properties to cartilage extracellular matrix but they are unable to meet the mechanical and biological requirements for a successful outcome. Here, we reinforce hyaluronic acid (HA) hydrogels with 13-93-lithium bioactive glass micro- and nanofibres produced by laser spinning. The glass fibres are a reinforcement filler and a platform for the delivery of therapeutic lithium-ions. The elastic modulus of the composites is more than three times higher than in HA hydrogels. Modelling of the reinforcement corroborates the experimental results. ATDC5 chondrogenic cells seeded on the composites are viable and more proliferation occurs on the hydrogels containing fibres than in HA hydrogels alone. Furthermore, the chondrogenic behavior on HA constructs with fibres containing lithium is more marked than in hydrogels with no-lithium fibres.Xunta de Galicia | Ref. ED431B 2016/042Xunta de Galicia | Ref. POS-A/2013/161Xunta de Galicia | Ref. ED481D 2017/010Xunta de Galicia | Ref. ED481B 2016/047-

The structural basis for Z α1-antitrypsin polymerization in the liver

The serpinopathies are among a diverse set of conformational diseases that involve the aberrant self-association of proteins into ordered aggregates. α1-Antitrypsin deficiency is the archetypal serpinopathy and results from the formation and deposition of mutant forms of α1-antitrypsin as “polymer” chains in liver tissue. No detailed structural analysis has been performed of this material. Moreover, there is little information on the relevance of well-studied artificially induced polymers to these disease-associated molecules. We have isolated polymers from the liver tissue of Z α1-antitrypsin homozygotes (E342K) who have undergone transplantation, labeled them using a Fab fragment, and performed single-particle analysis of negative-stain electron micrographs. The data show structural equivalence between heat-induced and ex vivo polymers and that the intersubunit linkage is best explained by a carboxyl-terminal domain swap between molecules of α1-antitrypsin

Why alternative teenagers self-harm: exploring the link between non-suicidal self-injury, attempted suicide and adolescent identity

Background: The term ‘self-harm’ encompasses both attempted suicide and non-suicidal self-injury (NSSI). Specific adolescent subpopulations such as ethnic or sexual minorities, and more controversially, those who identify as ‘Alternative’ (Goth, Emo) have been proposed as being more likely to self-harm, while other groups such as ‘Jocks’ are linked with protective coping behaviours (for example exercise). NSSI has autonomic (it reduces negative emotions) and social (it communicates distress or facilitates group ‘bonding’) functions. This study explores the links between such aspects of self-harm, primarily NSSI, and youth subculture.<p></p> Methods: An anonymous survey was carried out of 452 15 year old German school students. Measures included: identification with different youth cultures, i.e. Alternative (Goth, Emo, Punk), Nerd (academic) or Jock (athletic); social background, e.g. socioeconomic status; and experience of victimisation. Self-harm (suicide and NSSI) was assessed using Self-harm Behavior Questionnaire and the Functional Assessment of Self-Mutilation (FASM).<p></p> Results: An “Alternative” identity was directly (r ≈ 0.3) and a “Jock” identity inversely (r ≈ -0.1) correlated with self-harm. “Alternative” teenagers self-injured more frequently (NSSI 45.5% vs. 18.8%), repeatedly self-injured, and were 4–8 times more likely to attempt suicide (even after adjusting for social background) than their non-Alternative peers. They were also more likely to self-injure for autonomic, communicative and social reasons than other adolescents.<p></p> Conclusions: About half of ‘Alternative’ adolescents’ self-injure, primarily to regulate emotions and communicate distress. However, a minority self-injure to reinforce their group identity, i.e. ‘To feel more a part of a group’

Promoting the use of the PI-QUAL score for prostate MRI quality: results from the ESOR Nicholas Gourtsoyiannis teaching fellowship

OBJECTIVES: The Prostate Imaging Quality (PI-QUAL) score is a new metric to evaluate the diagnostic quality of multiparametric magnetic resonance imaging (MRI) of the prostate. This study assesses the impact of an intervention, namely a prostate MRI quality training lecture, on the participant's ability to apply PI-QUAL. METHODS: Sixteen participants (radiologists, urologists, physicists, and computer scientists) of varying experience in reviewing diagnostic prostate MRI all assessed the image quality of ten examinations from different vendors and machines. Then, they attended a dedicated lecture followed by a hands-on workshop on MRI quality assessment using the PI-QUAL score. Five scans assessed by the participants were evaluated in the workshop using the PI-QUAL score for teaching purposes. After the course, the same participants evaluated the image quality of a new set of ten scans applying the PI-QUAL score. Results were assessed using receiver operating characteristic analysis. The reference standard was the PI-QUAL score assessed by one of the developers of PI-QUAL. RESULTS: There was a significant improvement in average area under the curve for the evaluation of image quality from baseline (0.59 [95 % confidence intervals: 0.50-0.66]) to post-teaching (0.96 [0.92-0.98]), an improvement of 0.37 [0.21-0.41] (p < 0.001). CONCLUSIONS: A teaching course (dedicated lecture + hands-on workshop) on PI-QUAL significantly improved the application of this scoring system to assess the quality of prostate MRI examinations. KEY POINTS: • A significant improvement in the application of PI-QUAL for the assessment of prostate MR image quality was observed after an educational intervention. • Appropriate training on image quality can be delivered to those involved in the acquisition and interpretation of prostate MRI. • Further investigation will be needed to understand the impact on improving the acquisition of high-quality diagnostic prostate MR examinations