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Abstract Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood–brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition.

Introduction Team-based, interprofessional approaches to outpatient care are critical to high-quality patient care. However, few specific educational interventions promoting these skills in graduate level health care trainees have been described to date. Methods University of Minnesota faculty from the Schools of Medicine, Pharmacy, and Nursing created an interprofessional workshop experience exploring core concepts in outpatient care for graduate level trainees in pediatrics, family medicine, medicine-pediatrics, internal medicine, graduate-level nursing, and pharmacy. We focused on four key content areas: teamwork, systems thinking, the patient-centered health care home, and patient-centered communication. The workshop included brief didactics, role-plays, team-based experiences, and interactive skill practice. Participants completed an end-of-day survey reflecting on knowledge and attitude. Results From 2014–2017, nine workshops reached 305 trainees. Survey results from the 2015–2016 academic year are representative of our overall results and revealed that learners found the content high yield, and that they valued the opportunity to learn with their interprofessional colleagues. Improvements in perceived knowledge were noted in all domains. Trainees also reported increased skills, with 81% reporting both increased confidence in working within the interprofessional team, and change in attitude, and 90% reporting increased interest in working with their interprofessional colleagues after the workshop. Discussion Creating an opportunity for postgraduate level trainees from a variety of disciplines and professions to convene and focus on interprofessional team-based skills can fill a gap in interprofessional learning as they enter practice. Trainees were able to draw on their everyday experiences and find common ground with their interprofessional colleagues.

The three members of the ether-à-go-go-gene-like (Elk; Kv12.1-Kv12.3) family of voltage-gated K+ channels are predominantly expressed in neurons, but only little information is available on their physiological relevance. It was shown that Kv12.2 channels modulate excitability of hippocampal neurons, but no native current could be attributed to Kv12.1 and Kv12.3 subunits yet. This may appear somewhat surprising, given high expression of their mRNA transcripts in several brain areas. Native Kv12 currents may have been overlooked so far due to limited knowledge on their biophysical properties and lack of specific pharmacology. Except for Kv12.2, appropriate genetically modified mouse models have not been described; therefore, identification of Kv12-mediated currents in native cell types must rely on characterization of unique properties of the channels. We focused on recombinant human Kv12.1 to identify distinct properties of these channels. We found that Kv12.1 channels exhibited significant mode shift of activation, i.e., stabilization of the voltage sensor domain in a “relaxed” open state after prolonged channel activation. This mode shift manifested by a slowing of deactivation and, most prominently, a significant shift of voltage dependence to hyperpolarized potentials. In contrast to related Kv11.1, mode shift was not sensitive to extracellular Na+, which allowed for discrimination between these isoforms. Sensitivity of Kv12.1 and Kv11.1 to the broad-spectrum K+ antagonist 4-aminopyridine was similar. However, 4-AP strongly activated Kv12.1 channels, but it was an inhibitor of Kv11 channels. Interestingly, the agonist of Kv11 channels NS1643 also differentially modulated the activity of these channels, i.e., NS1643 activated Kv11.1, but strongly inhibited Kv12.1 channels. Thus, these closely related channels are distinguished by inverse pharmacological profiles. In summary, we identified unique biophysical and pharmacological properties of Kv12.1 channels and established straightforward experimental protocols to characterize Kv12.1-mediated currents. Identification of currents in native cell types with mode shift that are activated through 4-AP and inhibited by NS1643 can provide strong evidence for contribution of Kv12.1 to whole cell currents.

Biosensors for the detection of benzaldehyde and g-aminobutyric acid (GABA) are reported using aldehyde oxidoreductase PaoABC from Escherichia coli immobilized in a polymer containing bound low potential osmium redox complexes. The electrically connected enzyme already electrooxidizes benzaldehyde at potentials below −0.15 V (vs. Ag|AgCl, 1 M KCl). The pH-dependence of benzaldehyde oxidation can be strongly influenced by the ionic strength. The effect is similar with the soluble osmium redox complex and therefore indicates a clear electrostatic effect on the bioelectrocatalytic efficiency of PaoABC in the osmium containing redox polymer. At lower ionic strength, the pH-optimum is high and can be switched to low pH-values at high ionic strength. This offers biosensing at high and low pH-values. A “reagentless” biosensor has been formed with enzyme wired onto a screen-printed electrode in a flow cell device. The response time to addition of benzaldehyde is 30 s, and the measuring range is between 10–150 µM and the detection limit of 5 µM (signal to noise ratio 3:1) of benzaldehyde. The relative standard deviation in a series (n = 13) for 200 µM benzaldehyde is 1.9%. For the biosensor, a response to succinic semialdehyde was also identified. Based on this response and the ability to work at high pH a biosensor for GABA is proposed by coimmobilizing GABA-aminotransferase (GABA-T) and PaoABC in the osmium containing redox polymer.

Verzehrfertige Salate, Obstprodukte und Sprossen boomen. Allerdings bergen sie ein nicht unerhebliches Risiko einer Belastung mit Krankheitserregern. Warum lassen sich Einträge von pathogenen Bakterien trotz hoher Hygienestandards in den verarbeitenden Betrieben nicht vollständig vermeiden? An welchen Stellen der Warenketten erfolgen Kontaminationen und wie können sich die Erreger vermehren? Das vom BMBF im Rahmen des Programms „Forschung für die zivile Sicherheit“ geförderte Verbundprojekt SAFEFRESH hat erforscht, wie sich das mikrobielle Risiko bei Fresh-Cut-Erzeugnissen reduzieren lässt. Dazu wurden ein Monitoring- und verschiedene Entkeimungsverfahren entwickelt sowie realistische Szenarios zu möglichen Kontaminationsfällen und deren Folgekaskaden hergeleitet. Der Gewinn an zusätzlicher Sicherheit ist jedoch begrenzt.