Amphiphilic Cyclic Peptide [W\u3csub\u3e4\u3c/sub\u3eKR\u3csub\u3e5\u3c/sub\u3e]-Antibiotics Combinations as Broad-Spectrum Antimicrobial Agents

Linear and cyclic amphiphilic peptides, (W4KR5) and [W4KR5], were evaluated as antibacterial agents against Gram-positive and Gram-negative bacteria, including four multi-drug resistant strains and the corresponding four non-resistant strains. Cyclic peptide [W4KR5] showed higher antibacterial activity than the linear (W4KR5) counterpart. Cyclic [W4KR5] was subjected to combination (physical mixture or covalent conjugation) with meropenem as a model antibiotic to study the impact of the combination on antimicrobial activity. A physical mixture of meropenem and [W4KR5] showed synergistic antibacterial activity against Gram-negative P. aeruginosa (ATCC BAA-1744) and P. aeruginosa (ATCC 27883) strains. [W4KR5] was further subjected to extensive antibacterial studies against additional 10 bacteria strains, showing significant antibacterial efficacy against Gram-positive bacteria strains. Combinations studies of [W4KR5] with an additional 9 commercially available antibiotics showed significant enhancement in antibacterial activity for all tested combinations, especially with tetracycline, tobramycin, levofloxacin, clindamycin, daptomycin, polymyxin, kanamycin, and vancomycin. Time-kill kinetics assay and flow cytometry results exhibited that [W4KR5] had a time-dependent synergistic effect and membrane disruption property. These data indicate that [W4KR5] improves the antibacterial activity, presumably by facilitating the internalization of antibiotics and their interaction with the intracellular targets. This study introduces a potential strategy for treating multidrug-resistant pathogens by combining [W4KR5] and a variety of classical antibiotics to improve the antibacterial effectiveness

Membrane-Active Cyclic Amphiphilic Peptides: Broad-Spectrum Antibacterial Activity Alone and in Combination with Antibiotics

We designed a library of 24 cyclic peptides containing arginine (R) and tryptophan (W) residues in a sequential manner [RnWn] (n = 2–7) to study the impact of the hydrophilic/hydrophobic ratio, charge, and ring size on the antibacterial activity against Gram-positive and Gram-negative strains. Among peptides, 5a and 6a demonstrated the highest antimicrobial activity. In combination with 11 commercially available antibiotics, 5a and 6a showed remarkable synergism against a large panel of resistant pathogens. Hemolysis (HC50 = 340 μg/mL) and cell viability against mammalian cells demonstrated the selective lethal action of 5a against bacteria over mammalian cells. Calcein dye leakage and scanning electron microscopy studies revealed the membranolytic effect of 5a. Moreover, the stability in human plasma (t1/2 = 3 h) and the negligible ability of pathogens to develop resistance further reflect the potential of 5a for further development as a peptide-based antibiotic

Comparative Molecular Transporter Properties of Cyclic Peptides Containing Tryptophan and Arginine Residues Formed through Disulfide Cyclization

We have previously reported cyclic cell-penetrating peptides [WR]5 and [WR]4 as molecular transporters. To optimize further the utility of our developed peptides for targeted therapy in cancer cells using the redox condition, we designed a new generation of peptides and evaluated their cytotoxicity as well as uptake behavior against different cancer cell lines. Thus, cyclic [C(WR)xC] and linear counterparts (C(WR)xC), where x = 4–5, were synthesized using Fmoc/tBu solid-phase peptide synthesis, purified, and characterized. The compounds did not show any significant cytotoxicity (at 25 µM) against ovarian (SK-OV-3), leukemia (CCRF-CEM), gastric adenocarcinoma (CRL-1739), breast carcinoma (MDA-MB-231), and normal kidney (LLCPK) cells after 24 and 72 h incubation. Both cyclic [C(WR)5C] and linear (C(WR)5C) demonstrated comparable molecular transporter properties versus [WR]5 in the delivery of a phosphopeptide (F′-GpYEEI) in CCRF-CEM cells. The uptake of F′-GpYEEI in the presence of 1,4-dithiothreitol (DTT) as the reducing agent was significantly improved in case of l(C(WR)5C), while it was not changed by [C(WR)5C]. Fluorescence microscopy also demonstrated a significant uptake of F′-GpYEEI in the presence of l(C(WR)5C). Cyclic [C(WR)5C] improved the uptake of the fluorescent-labeled anti-HIV drugs F′-d4T, F′-3TC, and F′-FTC by 3.0–4.9-fold. These data indicate that both [C(WR)5C] and linear (C(WR)5C) peptides can act as molecular transporters

Training and evaluating simulation debriefers in low-resource settings: lessons learned from Bihar, India.

BACKGROUND: To develop effective and sustainable simulation training programs in low-resource settings, it is critical that facilitators are thoroughly trained in debriefing, a critical component of simulation learning. However, large knowledge gaps exist regarding the best way to train and evaluate debrief facilitators in low-resource settings. METHODS: Using a mixed methods approach, this study explored the feasibility of evaluating the debriefing skills of nurse mentors in Bihar, India. Videos of obstetric and neonatal post-simulation debriefs were assessed using two known tools: the Center for Advanced Pediatric and Perinatal Education (CAPE) tool and Debriefing Assessment for Simulation in Healthcare (DASH). Video data was used to evaluate interrater reliability and changes in debriefing performance over time. Additionally, twenty semi-structured interviews with nurse mentors explored perceived barriers and enablers of debriefing in Bihar. RESULTS: A total of 73 debriefing videos, averaging 18 min each, were analyzed by two raters. The CAPE tool demonstrated higher interrater reliability than the DASH; 13 of 16 CAPE indicators and two of six DASH indicators were judged reliable (ICC > 0.6 or kappa > 0.40). All indicators remained stable or improved over time. The number of 'instructors questions,' the amount of 'trainee responses,' and the ability to 'organize the debrief' improved significantly over time (p < 0.01, p < 0.01, p = 0.04). Barriers included fear of making mistakes, time constraints, and technical challenges. Enablers included creating a safe learning environment, using contextually appropriate debriefing strategies, and team building. Overall, nurse mentors believed that debriefing was a vital aspect of simulation-based training. CONCLUSION: Simulation debriefing and evaluation was feasible among nurse mentors in Bihar. Results demonstrated that the CAPE demonstrated higher interrater reliability than the DASH and that nurse mentors were able to maintain or improve their debriefing skills overtime. Further, debriefing was considered to be critical to the success of the simulation training. However, fear of making mistakes and logistical challenges must be addressed to maximize learning. Teamwork, adaptability, and building a safe learning environment enhanced the quality enhanced the quality of simulation-based training, which could ultimately help to improve maternal and neonatal health outcomes in Bihar

Lemaitre-Tolman-Bondi collapse from the perspective of loop quantum gravity

Lemaitre-Tolman-Bondi models as specific spherically symmetric solutions of general relativity simplify in their reduced form some of the mathematical ingredients of black hole or cosmological applications. The conditions imposed in addition to spherical symmetry turn out to take a simple form at the kinematical level of loop quantum gravity, which allows a discussion of their implications at the quantum level. Moreover, the spherically symmetric setting of inhomogeneity illustrates several non-trivial properties of lattice refinements of discrete quantum gravity. Nevertheless, the situation at the dynamical level is quite non-trivial and thus provides insights to the anomaly problem. At an effective level, consistent versions of the dynamics are presented which implement the conditions together with the dynamical constraints of gravity in an anomaly-free manner. These are then used for analytical as well as numerical investigations of the fate of classical singularities, including non-spacelike ones, as they generically develop in these models. None of the corrections used here resolve those singularities by regular effective geometries. However, there are numerical indications that the collapse ends in a tamer shell-crossing singularity prior to the formation of central singularities for mass functions giving a regular conserved mass density. Moreover, we find quantum gravitational obstructions to the existence of exactly homogeneous solutions within this class of models. This indicates that homogeneous models must be seen in a wider context of inhomogeneous solutions and their reduction in order to provide reliable dynamical conclusions.Comment: 56 pages, 42 figure

Role of positron emission tomography-computed tomography in bronchial mucoepidermoid carcinomas: a case series and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Mucoepidermoid carcinoma of the tracheobronchial tree is rare. Such tumors usually present with signs and symptoms of bronchial obstruction. Histologically, they can be classified as high-grade or low-grade tumors. Experience of imaging these tumors with ¹⁸fluorodeoxyglucose positron emission tomography-computed tomography (¹⁸F-FDG PET-CT) is limited. We present three cases of this rare tumor, describe the functional imaging results, and review the available literature.</p> <p>Case presentation</p> <p>Three Caucasian patients, two men (21 and 24 years of age) and one woman (14 years of age), with bronchial masses were evaluated by us. All three patients were symptomatic, and underwent a thorough clinical examination, bronchoscopy and biopsy, plain computed tomography, ¹⁸F-FDG PET-CT and ⁶⁸Gallium 1,4,7,10-Tetraazacyclododecane-N^I,N^II,N^III,N^IIII,- tetra acetic acid (D) - Phel¹-Tyr³-octreotide positron emission tomography-computed tomography (⁶⁸Ga-DOTATOC PET-CT). ¹⁸F-FDG PET-CT revealed mild uptake in all three patients, whereas ⁶⁸Ga-DOTATOC PET-CT revealed no significant uptake in any patient, making carcinoid tumor unlikely. Results of histopathological examination were consistent with low-grade mucoepidermoid carcinoma in all patients.</p> <p>Conclusion</p> <p>Our study reveals that functional imaging may be helpful in the initial investigation of patients with mucoepidermoid carcinoma. ¹⁸F-FDG PET-CT may have a prognostic relevance by predicting the histopathologic differentiation of the tumor.</p