Is COVID-19 perceived as a threat to equal career opportunities amongst Swiss medical students? A cross-sectional survey study from Bern and Geneva.

INTRODUCTION Students frequently rely on part-time jobs to earn a living wage. We sought to evaluate the sociodemographic status of Swiss medical students and their perception regarding equal career opportunities in view of impaired part-time job opportunities under the COVID-19 pandemic. METHODS We conducted an anonymous online survey among Swiss medical students from Bern and Geneva over a period of 4 months between December 2020 and April 2021. We evaluated sociodemographic data, current living situation, part-time job occupation as well as other sources of income to fund living expenses, and, by means of a five-point Likert scale (1=strongly disagree and 5=strongly agree), whether COVID-19 was perceived as impeding equal career opportunities. RESULTS Of 968 participants, corresponding to around 13.8% of all medical students in Switzerland, 81.3% had part-time jobs. Amongst the employed, 54.8% worked to afford living expenses and 28.9% reported a negative financial impact due to reduced part-time jobs under the pandemic. The loss of part-time jobs was perceived to make medical studies a privilege for students with higher socioeconomic status (4.11±1.0), whose opportunity to study is independent of a regular income. A governmental backup plan was considered crucial to support affected students (4.22±0.91). DISCUSSION COVID-19 and its sequelae are perceived as a threat for Swiss medical students and lead to a disadvantage for those with lower socioeconomic status. Nationwide measures should be established to foster equal career opportunities

Glued suture-less peritoneum closure in laparoscopic inguinal hernia repair reduces acute postoperative pain.

Inguinal hernia repair is performed more than 20 million times per annum, representing a significant health and economic burden. Over the last three decades, significant technical advances have started to reduce the invasiveness of these surgeries, which translated to better recovery and reduced costs. Here we bring forward an innovative surgical technique using a biodegradable cyanoacrylate glue instead of a traumatic suture to close the peritoneum, which is a highly innervated tissue layer, at the end of endoscopy hernia surgery. To test how this affects the invasiveness of hernia surgery, we conducted a cohort study. A total of 183 patients that underwent minimally invasive hernia repair, and the peritoneum was closed with either a conventional traumatic suture (n = 126, 68.9%) or our innovative approach using glue (n = 57, 31.1%). The proportion of patients experiencing acute pain after surgery was significantly reduced (36.8 vs. 54.0%, p = 0.032) by using glue instead of a suture. In accordance, the mean pain level was higher in the suture group (VAS = 1.5 vs. 1.3, p = 0.029) and more patients were still using painkillers (77.9 vs. 52.4%, p = 0.023). Furthermore, the rate of complications was not increased in the glue group. Using multivariate regressions, we identified that using a traumatic suture was an independent predictor of acute postoperative pain (OR 2.0, 95% CI 1.1-3.9, p = 0.042). In conclusion, suture-less glue closure of the peritoneum is innovative, safe, less painful, and possibly leads to enhanced recovery and decreased health costs

Mechanism-based traps enable protease and hydrolase substrate discovery.

Hydrolase enzymes, including proteases, are encoded by 2-3% of the genes in the human genome and 14% of these enzymes are active drug targets1. However, the activities and substrate specificities of many proteases-especially those embedded in membranes-and other hydrolases remain unknown. Here we report a strategy for creating mechanism-based, light-activated protease and hydrolase substrate traps in complex mixtures and live mammalian cells. The traps capture substrates of hydrolases, which normally use a serine or cysteine nucleophile. Replacing the catalytic nucleophile with genetically encoded 2,3-diaminopropionic acid allows the first step reaction to form an acyl-enzyme intermediate in which a substrate fragment is covalently linked to the enzyme through a stable amide bond2; this enables stringent purification and identification of substrates. We identify new substrates for proteases, including an intramembrane mammalian rhomboid protease RHBDL4 (refs. 3,4). We demonstrate that RHBDL4 can shed luminal fragments of endoplasmic reticulum-resident type I transmembrane proteins to the extracellular space, as well as promoting non-canonical secretion of endogenous soluble endoplasmic reticulum-resident chaperones. We also discover that the putative serine hydrolase retinoblastoma binding protein 9 (ref. 5) is an aminopeptidase with a preference for removing aromatic amino acids in human cells. Our results exemplify a powerful paradigm for identifying the substrates and activities of hydrolase enzymes

Mechanism-based traps enable protease and hydrolase substrate discovery.

Hydrolase enzymes, including proteases, are encoded by 2-3% of the genes in the human genome and 14% of these enzymes are active drug targets1. However, the activities and substrate specificities of many proteases-especially those embedded in membranes-and other hydrolases remain unknown. Here we report a strategy for creating mechanism-based, light-activated protease and hydrolase substrate traps in complex mixtures and live mammalian cells. The traps capture substrates of hydrolases, which normally use a serine or cysteine nucleophile. Replacing the catalytic nucleophile with genetically encoded 2,3-diaminopropionic acid allows the first step reaction to form an acyl-enzyme intermediate in which a substrate fragment is covalently linked to the enzyme through a stable amide bond2; this enables stringent purification and identification of substrates. We identify new substrates for proteases, including an intramembrane mammalian rhomboid protease RHBDL4 (refs. 3,4). We demonstrate that RHBDL4 can shed luminal fragments of endoplasmic reticulum-resident type I transmembrane proteins to the extracellular space, as well as promoting non-canonical secretion of endogenous soluble endoplasmic reticulum-resident chaperones. We also discover that the putative serine hydrolase retinoblastoma binding protein 9 (ref. 5) is an aminopeptidase with a preference for removing aromatic amino acids in human cells. Our results exemplify a powerful paradigm for identifying the substrates and activities of hydrolase enzymes

Mechanism-based traps enable protease and hydrolase substrate discovery.

Hydrolase enzymes, including proteases, are encoded by 2-3% of the genes in the human genome and 14% of these enzymes are active drug targets1. However, the activities and substrate specificities of many proteases-especially those embedded in membranes-and other hydrolases remain unknown. Here we report a strategy for creating mechanism-based, light-activated protease and hydrolase substrate traps in complex mixtures and live mammalian cells. The traps capture substrates of hydrolases, which normally use a serine or cysteine nucleophile. Replacing the catalytic nucleophile with genetically encoded 2,3-diaminopropionic acid allows the first step reaction to form an acyl-enzyme intermediate in which a substrate fragment is covalently linked to the enzyme through a stable amide bond2; this enables stringent purification and identification of substrates. We identify new substrates for proteases, including an intramembrane mammalian rhomboid protease RHBDL4 (refs. 3,4). We demonstrate that RHBDL4 can shed luminal fragments of endoplasmic reticulum-resident type I transmembrane proteins to the extracellular space, as well as promoting non-canonical secretion of endogenous soluble endoplasmic reticulum-resident chaperones. We also discover that the putative serine hydrolase retinoblastoma binding protein 9 (ref. 5) is an aminopeptidase with a preference for removing aromatic amino acids in human cells. Our results exemplify a powerful paradigm for identifying the substrates and activities of hydrolase enzymes

Mitotic spindle association of TACC3 requires Aurora-A-dependent stabilization of a cryptic α-helix.

Aurora-A regulates the recruitment of TACC3 to the mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe the structural basis of these interactions, mediated by three motifs in a disordered region of TACC3. A hydrophobic docking motif binds to a previously uncharacterized pocket on Aurora-A that is blocked in most kinases. Abrogation of the docking motif causes a delay in late mitosis, consistent with the cellular distribution of Aurora-A complexes. Phosphorylation of Ser558 engages a conformational switch in a second motif from a disordered state, needed to bind the kinase active site, into a helical conformation. The helix extends into a third, adjacent motif that is recognized by a helical-repeat region of CHC, not a recognized phospho-reader domain. This potentially widespread mechanism of phospho-recognition provides greater flexibility to tune the molecular details of the interaction than canonical recognition motifs that are dominated by phosphate binding

Wird COVID-19 von den Medizinstudierenden in der Schweiz als Bedrohung für die Chancengleichheit zur Erlangung des Berufes wahrgenommen? Eine Querschnittsstudie aus Bern und Genf

Introduction: Students frequently rely on part-time jobs to earn a living wage. We sought to evaluate the sociodemographic status of Swiss medical students and their perception regarding equal career opportunities in view of impaired part-time job opportunities under the COVID-19 pandemic.Methods: We conducted an anonymous online survey among Swiss medical students from Bern and Geneva over a period of 4 months between December 2020 and April 2021. We evaluated sociodemographic data, current living situation, part-time job occupation as well as other sources of income to fund living expenses, and, by means of a five-point Likert scale (1=strongly disagree and 5=strongly agree), whether COVID-19 was perceived as impeding equal career opportunities.Results: Of 968 participants, corresponding to around 13.8% of all medical students in Switzerland, 81.3% had part-time jobs. Amongst the employed, 54.8% worked to afford living expenses and 28.9% reported a negative financial impact due to reduced part-time jobs under the pandemic. The loss of part-time jobs was perceived to make medical studies a privilege for students with higher socioeconomic status (4.11±1.0), whose opportunity to study is independent of a regular income. A governmental backup plan was considered crucial to support affected students (4.22±0.91).Discussion: COVID-19 and its sequelae are perceived as a threat for Swiss medical students and lead to a disadvantage for those with lower socioeconomic status. Nationwide measures should be established to foster equal career opportunities.Einleitung: Studierende sind häufig auf Nebenjobs angewiesen, um ihren Lebensunterhalt zu bestreiten. Wir untersuchten den soziodemographischen Status von Schweizer Medizinstudierenden und deren Einschätzung, ob reduzierte Teilzeitarbeitsmöglichkeiten im Rahmen der COVID-19-Pandemie eine Bedrohung der Chancengleichheit zur Erlangung des Berufes darstellt.Methoden: Wir unternahmen eine anonyme Online-Umfrage unter Schweizer Medizinstudierenden aus Bern und Genf über einen Zeitraum von 4 Monaten zwischen Dezember 2020 und April 2021. Abgefragt wurden soziodemografische Daten, die aktuelle Lebenssituation, Teilzeitbeschäftigung sowie etwaige weitere Einkommensquellen zur Finanzierung des Lebensunterhalts. Zudem wurde mittels einer fünfstufigen Likert-Skala (1=stimmt überhaupt nicht zu, 5=stimmt voll und ganz zu) abgefragt, ob die Auswirkung der COVID-19-Pandemie hierauf als Beeinträchtigung der beruflichen Chancengleichheit wahrgenommen wird.Ergebnisse: Von den 968 Teilnehmenden, die rund 13,8% aller Medizinstudierenden in der Schweiz darstellen, hatten 81,3% einen Teilzeitjob. Von den Erwerbstätigen arbeiteten 54,8% neben dem Studium, um den Lebensunterhalt zu bestreiten, wobei 28,9 % über negative finanzielle Auswirkungen aufgrund der reduzierten Teilzeitstellen während der Pandemie berichteten. Der Verlust von Teilzeitjobs machte das Medizinstudium aus Sicht der Studierenden zu einem Privileg für Studierende mit höherem sozioökonomischem Status (4,11±1,0), deren Möglichkeit zu studieren eher unabhängig von einem regelmäßigen Einkommen ist. Ein staatlicher Notfallplan für betroffene Studierende wurde dabei als wichtige Massnahme zur Unterstützung angesehen (4,22±0,91).Diskussion: Die COVID-19-Pandemie und ihre Folgen werden von den Befragten als Bedrohung wahrgenommen und bringen eine Benachteiligung für Schweizer Medizinstudierende mit niedrigerem sozioökonomischem Status. Es sollten gesamtschweizerische Massnahmen zur Förderung der beruflichen Chancengleichheit ergriffen werden

Site-Specific Traceless Coupling of Potent Cytotoxic Drugs to Recombinant Antibodies for Pharmacodelivery

Aldehyde drugs are gaining increasing research interest, considering that aldehyde dehydrogenases overexpression is characteristic of cancer stem cells. Here, we describe the traceless site-specific coupling of a novel potent drug, containing an aldehyde moiety, to recombinant antibodies, which were engineered to display a cysteine residue at their N-terminus, or a 1,2-aminothiol at their C-terminus. The resulting chemically defined antibody-drug conjugates represent the first example in which a thiazolidine linkage is used for the targeted delivery and release of cytotoxic agents

L’union fait la force :traitement des troubles fonctionnels complexes à l’adolescence [Together we are stronger: management of complex functional disorders during adolescence]

Functional disorder during adolescence is a very complex problem too often limited to a psychological origin. Its pathogenesis remains unclear but it definitively associates individual and environmental factors. Recent data show anatomo-functional evidence of neural networks of the brain that is involved in pain and its psychological representation as well as the representation of pain in the body. We describe a holistic approach to manage functional disorders that include the family and promote adolescent centered care in order to reach a rapid and optimal rehabilitation