From Observers to Participants: Joining the Scientific Community

In this essay, we have integrated the voices of our mentors and students to explore 45 years of undergraduate research experiences and their role in shaping our scientific community. In considering our collective experiences, we see undergraduate involvement in research as a rich source of community development, one that has both touched our lives and influenced our teaching

Vergleich aktiv und passiv beschichteter Stents im Hinblick auf Restenoseprophylaxe - eine vergleichende tierexperimentelle Studie

Zusammenfassend kann aus dieser Studie entnommen werden, dass der getestete Ramapycin-Stent (+ Camouflage® Nanocoating) in der Lage ist die Neointimaproliferation und damit die Gefahr der Restenose signifikant zu senken. Weiterhin scheint dieser Stent durch seine antithrombogene Beschichtung in der Lage zu sein die Einheilung in die Gefäßwand zu verbessern, was möglicherweise durch die verbesserte vaskuläre Einheilung zu weniger Stentthrombosen führt. Die bessere Biokompatibilität und die damit verbundene verbesserte Einheilung könnten außerdem dazu führen, dass die momentan noch zwingend notwendige antikoagulative Therapie verkürzt oder herunterdosiert werden kann. Durch die Beschichtung mit Camouflage® Nanocoating ist es gelungen die erzielte Senkung der Restenosen durch eine besonders gute Biokompatibilität zu ergänzen. Gemeinsam sind diese beiden Komponenten möglicherweise in der Lage eine wiederholt verminderte Rate an Restenosen und Stentthrombosen zu erzielen. Weiteren Forschungsbedarf gibt es an vielen Stellen. Diese Studie ist als Pilotstudie anzusehen, die eine Möglichkeit der Verbesserung in der Therapie von Arteriosklerose im weitesten Sinne aufzeigt. Zukünftige Studien müssen evaluieren, ob 1. Sirolimus tatsächlich der optimale Wirkstoff ist, ob 2. das verwandte Polymer die beste Bioverträglichkeit hat und ob 3. die Eigenschaften des Stentgerüstes noch weiter optimiert werden können. Der Konkurrenzkampf zwischen PES und SES ist noch immer nicht endgültig entschieden und weitere Wirkstoffe wie Everolimus und Zotarolimus müssen ebenso evaluiert werden, wie neue Konzepte, die ohne Polymere auskommen oder komplett biodegenerable sind. Ebenso bieten DEB möglicherweise eine attraktive Alternative zu den bestehenden Therapiemöglichkeiten. Es sollten in Zukunft Studien durchgeführt werden, die eine genaue Evaluation der „neointimal coverage“ und der Inzidenz von Stenthrombosen vornehmen und auch deren molekulare Ursachen genauer erforschen, um die Überlegenheit des Rapamycin-Stents ( + Camouflage®) weiter zu festigen. Auch das Stentmaterial sollte noch einmal gesondert evaluiert werden. Es wären Studien sinnvoll, die BMS und DES mit dem Camouflage®-Stent vergleichen. Weiterhin sollte der Rapamycin-Stent (+Camouflage®) mit BMS und SES (ohne Camouflagebeschichtung) verglichen werden. Dies wäre sinnvoll, um die vielen Variablen zu minimieren und exaktere Daten für die Weiterentwicklung der DES zu generieren. Wenn die präklinische Phase abgeschlossen ist, muss das Konzept Rapamycin (+ Camouflage®) in der praktischen Anwendung am Patienten ebenfalls seine Wirksamkeit unter Beweis stellen. Erst dann können endgültige Aussagen zur Überlegenheit dieses Konzeptes gegenüber herkömmlichen Stents und konkurrierenden Verfahren gemacht werden

Optical detection of di- and triphosphate anions with mixed monolayer-protected gold nanoparticles containing zinc(II)–dipicolylamine complexes

Gold nanoparticles covered with a mixture of ligands of which one type contains solubilizing triethylene glycol residues and the other peripheral zinc(II)–dipicolylamine (DPA) complexes allowed the optical detection of hydrogenphosphate, diphosphate, and triphosphate anions in water/methanol 1:2 (v/v). These anions caused the bright red solutions of the nanoparticles to change their color because of nanoparticle aggregation followed by precipitation, whereas halides or oxoanions such as sulfate, nitrate, or carbonate produced no effect. The sensitivity of phosphate sensing depended on the nature of the anion, with diphosphate and triphosphate inducing visual changes at significantly lower concentrations than hydrogenphosphate. In addition, the sensing sensitivity was also affected by the ratio of the ligands on the nanoparticle surface, decreasing as the number of immobilized zinc(II)–dipicolylamine groups increased. A nanoparticle containing a 9:1 ratio of the solubilizing and the anion-binding ligand showed a color change at diphosphate and triphosphate concentrations as low as 10 μmol/L, for example, and precipitated at slightly higher concentrations. Hydrogenphosphate induced a nanoparticle precipitation only at a concentration of ca. 400 μmol/L, at which the precipitates formed in the presence of diphosphates and triphosphates redissolved. A nanoparticle containing fewer binding sites was more sensitive, while increasing the relative number of zinc(II)–dipicolylamine complexes beyond 25% had a negative impact on the limit of detection and the optical response. Transmission electron microscopy provided evidence that the changes of the nanoparticle properties observed in the presence of the phosphates were due to a nanoparticle crosslinking, consistent with the preferred binding mode of zinc(II)–dipicolylamine complexes with phosphate anions which involves binding of the anion between two metal centers. This work thus provided information on how the behavior of mixed monolayer-protected gold nanoparticles is affected by multivalent interactions, at the same time introducing a method to assess whether certain biologically relevant anions are present in an aqueous solution within a specific concentration range

Guidelines and considerations for the use of system suitability and quality control samples in mass spectrometry assays applied in untargeted clinical metabolomic studies

Background Quality assurance (QA) and quality control (QC) are two quality management processes that are integral to the success of metabolomics including their application for the acquisition of high quality data in any high-throughput analytical chemistry laboratory. QA defines all the planned and systematic activities implemented before samples are collected, to provide confidence that a subsequent analytical process will fulfil predetermined requirements for quality. QC can be defined as the operational techniques and activities used to measure and report these quality requirements after data acquisition. Aim of review This tutorial review will guide the reader through the use of system suitability and QC samples, why these samples should be applied and how the quality of data can be reported. Key scientific concepts of review System suitability samples are applied to assess the operation and lack of contamination of the analytical platform prior to sample analysis. Isotopically-labelled internal standards are applied to assess system stability for each sample analysed. Pooled QC samples are applied to condition the analytical platform, perform intra-study reproducibility measurements (QC) and to correct mathematically for systematic errors. Standard reference materials and long-term reference QC samples are applied for inter-study and inter-laboratory assessment of data

Intraoperative Defibrillation Testing of Subcutaneous Implantable Cardioverter‐Defibrillator Systems—A Simple Issue?

Background: The results of the recently published randomized SIMPLE trial question the role of routine intraoperative defibrillation testing. However, testing is still recommended during implantation of the entirely subcutaneous implantable cardioverter‐defibrillator (S‐ICD) system. To address the question of whether defibrillation testing in S‐ICD systems is still necessary, we analyzed the data of a large, standard‐of‐care prospective single‐center S‐ICD registry. // Methods and Results: In the present study, 102 consecutive patients received an S‐ICD for primary (n=50) or secondary prevention (n=52). Defibrillation testing was performed in all except 4 patients. In 74 (75%; 95% CI 0.66–0.83) of 98 patients, ventricular fibrillation was effectively terminated by the first programmed internal shock. In 24 (25%; 95% CI 0.22–0.44) of 98 patients, the first internal shock was ineffective and further internal or external shock deliveries were required. In these patients, programming to reversed shock polarity (n=14) or repositioning of the sensing lead (n=1) or the pulse generator (n=5) led to successful defibrillation. In 4 patients, a safety margin of <10 J was not attained. Nevertheless, in these 4 patients, ventricular arrhythmias were effectively terminated with an internal 80‐J shock. // Conclusions: Although it has been shown that defibrillation testing is not necessary in transvenous ICD systems, it seems particular important for S‐ICD systems, because in nearly 25% of the cases the primary intraoperative test was not successful. In most cases, a successful defibrillation could be achieved by changing shock polarity or by optimizing the shock vector caused by the pulse generator or lead repositioning.<br

Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections

Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (Mpro), its moderate activity in Mpro inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin’s efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1 mg/kg body weight reduces the viral load in the trachea. Despite a higher risk of side effects, an intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets. Here we show that the inhibition of cathepsins, a protein family of the host organism, by calpeptin is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections

The German National Pandemic Cohort Network (NAPKON): rationale, study design and baseline characteristics

Schons M, Pilgram L, Reese J-P, et al. The German National Pandemic Cohort Network (NAPKON): rationale, study design and baseline characteristics. European Journal of Epidemiology . 2022.The German government initiated the Network University Medicine (NUM) in early 2020 to improve national research activities on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. To this end, 36 German Academic Medical Centers started to collaborate on 13 projects, with the largest being the National Pandemic Cohort Network (NAPKON). The NAPKON's goal is creating the most comprehensive Coronavirus Disease 2019 (COVID-19) cohort in Germany. Within NAPKON, adult and pediatric patients are observed in three complementary cohort platforms (Cross-Sectoral, High-Resolution and Population-Based) from the initial infection until up to three years of follow-up. Study procedures comprise comprehensive clinical and imaging diagnostics, quality-of-life assessment, patient-reported outcomes and biosampling. The three cohort platforms build on four infrastructure core units (Interaction, Biosampling, Epidemiology, and Integration) and collaborations with NUM projects. Key components of the data capture, regulatory, and data privacy are based on the German Centre for Cardiovascular Research. By April 01, 2022, 34 university and 40 non-university hospitals have enrolled 5298 patients with local data quality reviews performed on 4727 (89%). 47% were female, the median age was 52 (IQR 36-62-) and 50 pediatric cases were included. 44% of patients were hospitalized, 15% admitted to an intensive care unit, and 12% of patients deceased while enrolled. 8845 visits with biosampling in 4349 patients were conducted by April 03, 2022. In this overview article, we summarize NAPKON's design, relevant milestones including first study population characteristics, and outline the potential of NAPKON for German and international research activities.Trial registration https://clinicaltrials.gov/ct2/show/NCT04768998 . https://clinicaltrials.gov/ct2/show/NCT04747366 . https://clinicaltrials.gov/ct2/show/NCT04679584. © 2022. The Author(s)

A course-based research experience: how benefits change with increased investment in instructional time

There is widespread agreement that science, technology, engineering, and mathematics programs should provide undergraduates with research experience. Practical issues and limited resources, however, make this a challenge. We have developed a bioinformatics project that provides a course-based research experience for students at a diverse group of schools and offers the opportunity to tailor this experience to local curriculum and institution-specific student needs. We assessed both attitude and knowledge gains, looking for insights into how students respond given this wide range of curricular and institutional variables. While different approaches all appear to result in learning gains, we find that a significant investment of course time is required to enable students to show gains commensurate to a summer research experience. An alumni survey revealed that time spent on a research project is also a significant factor in the value former students assign to the experience one or more years later. We conclude: 1) implementation of a bioinformatics project within the biology curriculum provides a mechanism for successfully engaging large numbers of students in undergraduate research; 2) benefits to students are achievable at a wide variety of academic institutions; and 3) successful implementation of course-based research experiences requires significant investment of instructional time for students to gain full benefit

Massive X-ray screening reveals two allosteric drug binding sites of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of repurposing drug libraries containing 5953 individual compounds against the SARS-CoV-2 main protease (Mpro), which is a potent drug target as it is essential for the virus replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. Interestingly, two compounds bind outside the active site to the native dimer interface in close proximity to the S1 binding pocket. Another compound binds in a cleft between the catalytic and dimerization domain of Mpro. Neither binding site is related to the enzymatic active site and both represent attractive targets for drug development against SARS-CoV-2. This X-ray screening approach thus has the potential to help deliver an approved drug on an accelerated time-scale for this and future pandemics