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Proline-rich antimicrobial peptides (PrAMPs) kill bacteria by binding in the ribosomal nascent peptide exit tunnel. Type II PrAMPs bind in an orientation matching that of the nascent protein, trap the release factors and arrest ribosomes at stop codons. Conversely, Type I PrAMPs bind in an opposite orientation: their N-terminus invades the peptidyl transferase center arresting translation at start codons. Here, by mining the genome databases, we identify a number of PrAMPs with high sequence similarity to the Type II PrAMP Drosocin. Notably, many of the new PrAMPs do not stall ribosomes at stop codons, but act as Type I PrAMPs arresting translation at start codons. Structural analysis shows that such peptides bind with a Type I orientation. Minimal alterations in the peptide structure can flip the orientation of the PrAMP in the exit tunnel, switching the mechanism of translation inhibition. Altering the mode of binding and action of a PrAMP by only few mutations could be exploited by the host to combat newly emerging bacterial pathogens. In this work authors show how minimal mutations in proline-rich antimicrobial peptides can flip their orientation in the ribosome exit tunnel, switching their mechanism from stalling translation termination to halting initiation - revealing a possible host strategy against evolving pathogens.

The paenilamicins are a group of hybrid nonribosomal peptide–polyketide compounds produced by the honey bee pathogen Paenibacillus larvae that display activity against Gram-positive pathogens, such as Staphylococcus aureus . While paenilamicins have been shown to inhibit protein synthesis, their mechanism of action has remained unclear. Here we determine structures of paenilamicin PamB2-stalled ribosomes, revealing a unique binding site on the small 30S subunit located between the A- and P-site transfer RNAs (tRNAs). In addition to providing a precise description of interactions of PamB2 with the ribosome, the structures also rationalize the resistance mechanisms used by P. larvae . We further demonstrate that PamB2 interferes with the translocation of messenger RNA and tRNAs through the ribosome during translation elongation, and that this inhibitory activity is influenced by the presence of modifications at position 37 of the A-site tRNA. Collectively, our study defines the paenilamicins as a class of context-specific translocation inhibitors. The paenilamicins are hybrid nonribosomal peptide–polyketide compounds that inhibit protein synthesis. Here the authors reveal that paenilamicins bind to a unique site on the ribosome, where they interfere with the translocation of mRNA and tRNAs during elongation.

Introduction: Coronavirus 2019 (COVID-19) accelerated the need for virtual learning including telesimulation. Many emergency medicine (EM) programs halted in-person simulation and trialed telesimulation, but specifics on its utilization and plans for future use are unknown. Telesimulation has been defined as “a process by which telecommunication and simulation resources are utilized to provide education, training, and/or assessment to learners at an off-site location.” Our objective in this study was to describe the patterns of telesimulation usage in EM residency programs during COVID-19-induced learning restrictions as well as its anticipated future utility. Methods: We identified EM simulation leaders via the EMRA Match website, institutional websites, or personal contact with residency coordinators and directors, and invited them to participate by email. Participants completed a confidential, web-based survey consisting of multiple-choice items and one free-response question, developed by our study team with consideration of survey research best practices and Messick’s validity framework. We collected data between January–February 2022. We calculated descriptive statistics for multiple-choice items and examined the free-response answers for common themes. Results: We obtained contact information for simulation leaders at 139 EM residency programs. Survey response rate was 65% (91/139). During in-person restrictions, 62% (56/91) of programs used telesimulation. Assuming all restrictions lifted, 38% (34/90) of respondents planned to continue to use telesimulation, compared to 9% (8/91) using telesimulation before COVID-19. Most respondents planned to use telesimulation for medical knowledge (26/34, 76%) and communication/teamwork-focused cases (23/34, 68%). In response to the free-response question regarding experience with and plans for use, we identified three major themes: 1) telesimulation is a valuable alternative to in-person learning; 2) telesimulation is an option for learners unable to participate in person; and 3) telesimulation is challenging for procedural education. Conclusion: Despite the relatively limited use of telesimulation in EM residencies prior to COVID-19, an increased number of programs have plans to continue incorporating telesimulation into their curricula. This plan for continued use opens opportunities for further innovation and scholarship within simulation education.

Background: Rehabilitation after repair of the anterior cruciate ligament (ACL) is complicated by the loss of leg muscle mass and strength. Prior studies have shown that preoperative rehabilitation may improve muscle strength and postoperative outcomes. Testosterone supplementation may likewise counteract this muscle loss and potentially improve clinical outcomes. Purpose: The purpose was to investigate the effect of perioperative testosterone administration on lean mass after ACL reconstruction in men and to examine the effects of testosterone on leg strength and clinical outcome scores. It was hypothesized that testosterone would increase lean mass and leg strength and improve clinical outcome scores relative to placebo. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Male patients (N = 13) scheduled for ACL reconstruction were randomized into 2 groups: testosterone and placebo. Participants in the testosterone group received 200 mg of intramuscular testosterone weekly for 8 weeks beginning 2 weeks before surgery. Participants in the placebo group received saline following the same schedule. Both groups participated in a standard rehabilitation protocol. The primary outcome was the change in total lean body mass at 6 and 12 weeks. Secondary outcomes were extensor muscle strength, Tegner activity score, and Knee injury and Osteoarthritis Outcome Score. Results: There was an increase in lean mass of a mean 2.7 ± 1.7 kg at 6 weeks postoperatively in the testosterone group compared with a decrease of a mean 0.1 ± 1.5 kg in the placebo group (P = .01). Extensor muscle strength of the uninjured leg also increased more from baseline in the testosterone group (+20.8 ± 25.6 Nm) compared with the placebo group (–21.4 ± 36.7 Nm) at 12 weeks (P = .04). There were no significant between-group differences in injured leg strength or clinical outcome scores. There were no negative side effects of testosterone noted. Conclusion: Perioperative testosterone supplementation increased lean mass 6 weeks after ACL reconstruction, suggesting that this treatment may help minimize the effects of muscle atrophy associated with ACL injuries and repair. This study was not powered to detect differences in strength or clinical outcome scores to assess the incidence of testosterone-related adverse events. Clinical Relevance: Supraphysiological testosterone supplementation may be a useful adjunct therapy for counteracting muscle atrophy after ACL reconstruction. Further investigation is necessary to determine the safety profile and effects of perioperative testosterone administration on leg strength and clinical outcomes after surgery. Registration: NCT01595581 (ClinicalTrials.gov).

The decarbonization of the heat supply is crucial for the German energy transition. Integrating Power-to-Heat technologies like heat pumps (HPs) into district heating grids (DHGs) can support this process. The efficiency of HPs can be increased through temperature reduction in the DHG, though decentralized reheating may be required to supply sufficient heat for the end consumers. In order to investigate the associated trade-off, this study evaluates the economic, ecological, and technical effects of temperature reduction in DHGs using the software tool nPro. In a three-step process heat demand, the DHG design and operation are modeled. Three operating temperature scenarios are considered: 60 °C, 50 °C, and an ambient dependent flow temperature varying between 40 and 50 °C. As the temperatures decrease, the balance shifts between centrally produced HP heat and decentralized heat from instantaneous electric water heaters (IEWHs). The initial temperature reduction leads to reduced CO2 emissions, primary energy demand, heat losses, and total annual cost (TAC). However, with a further reduction in the operating temperature, an increase in these parameters occurs. While the necessary cost and primary energy for central components decrease, an increase in the decentralized heat generation is necessary to properly supply the heat demand. This leads to higher TAC and CO2 emissions overall.

The proline-rich antimicrobial peptide (PrAMP) drosocin is produced by Drosophila species to combat bacterial infection. Unlike many PrAMPs, drosocin is O-glycosylated at threonine 11, a post-translation modification that enhances its antimicrobial activity. Here we demonstrate that the O-glycosylation not only influences cellular uptake of the peptide but also interacts with its intracellular target, the ribosome. Cryogenic electron microscopy structures of glycosylated drosocin on the ribosome at 2.0–2.8-Å resolution reveal that the peptide interferes with translation termination by binding within the polypeptide exit tunnel and trapping RF1 on the ribosome, reminiscent of that reported for the PrAMP apidaecin. The glycosylation of drosocin enables multiple interactions with U2609 of the 23S rRNA, leading to conformational changes that break the canonical base pair with A752. Collectively, our study reveals novel molecular insights into the interaction of O-glycosylated drosocin with the ribosome, which provide a structural basis for future development of this class of antimicrobials. Koller et al. determined structures of the O-glycosylated antimicrobial peptide drosocin from Drosophila melanogaster in complex with the bacterial ribosome, revealing the mechanism by which drosocin inhibits the termination phase of protein synthesis.

Objectives: Surgical reconstruction of the anterior cruciate ligament (ACL) is essential for those who wish to resume athletic activity following ACL rupture. However, the trauma of surgical repair and post-operative immobility can exacerbate muscle loss and strength. This study investigated the effect of perioperative testosterone administration on lean mass recovery following ACL reconstruction in men. The effects of testosterone on leg strength and clinical outcome scores were also investigated. We hypothesized that testosterone would increase lean mass and leg strength, and improve clinical outcome scores 6 and 12 weeks after surgery to a greater degree than placebo. Methods: This was a randomized, controlled, double blinded clinical trial comparing testosterone and placebo for recovery from ACL repair. Thirteen male subjects scheduled for ACL reconstruction were randomized into two groups, testosterone (n=6) and placebo (n=7). Participants in the testosterone group received 200 mg of testosterone administration weekly for 8 weeks starting 2 weeks prior to surgery. Participants in the control group received a saline placebo intramuscularly following the same schedule. Both intervention groups underwent standard physical rehabilitation. The primary outcome was change in total lean body mass at 6 and 12 weeks, measured by whole-body dual-energy x-ray absorptiometry. Secondary outcomes were extensor muscle strength measured using a Cybex Dynamometer, and the Tegner Activity Score (TAS) and Knee Injury and Osteoarthritis Outcome Score (KOOS). Results: Total testosterone levels in the blood increased from baseline to an average of 860 ± 254 ng/dL by 1 day prior to surgery and 746 ± 173 ng/dL at 6 weeks post-surgery for the testosterone group. The differences in serum testosterone levels between the placebo and testosterone groups at 1 day prior to surgery and 6 weeks post-surgery were both statistically significant (p<0.001). We found that testosterone increased lean mass by 2.8 ± 1.7 kg from baseline at 6 weeks following surgery, while the placebo group had a decrease in lean muscle mass of 0.1 ± 1.5 kg (p=0.01) (Figure 1). Extensor strength of the non-injured leg had a greater increase from baseline in the testosterone group (20.8 ± 25.6 Nm) than the placebo group (-21.4 ± 36.7 Nm) at 12 weeks (p=0.02). There were no significant differences in injured leg strength or clinical outcome scores throughout the study period. Conclusion: Despite a catabolic environment, acute testosterone supplementation increased lean mass 6 weeks after ACL reconstruction, and strength of the non-injured leg 12 weeks after surgery, to a greater degree than placebo. These results suggest that testosterone may be a novel, useful adjunct to physical therapy for knee surgery rehabilitation by offsetting perioperative muscle loss from surgery and immobility. Larger studies are now necessary to elucidate the effects of perioperative testosterone administration on injured leg strength and clinical outcomes following surgery.