Small, anionic, and charge-neutralizing propeptide fragments of zymogens are antimicrobial

Some inactive precursor proteins, or zymogens, contain small, amino terminus, homopolymeric regions of Asp that neutralize the cationic charge of the active protein during synthesis. After posttranslational cleavage, the anionic propeptide fragment may exhibit antimicrobial activity. To demonstrate this, ovine trypsinogen activation peptide, and frog (Xenopus laevis) PYL activation peptide, both containing homopolymeric regions of Asp, were synthesized and tested against previously described surfactant-associated anionic peptide. Peptides inhibited the growth of both gram-negative (MIC, 0.08 to 3.00 mM) and gram-positive (MIC, 0.94 to 2.67 mM) bacteria. Small, anionic, and charge-neutralizing propeptide fragments of zymogens form a new class of host-derived antimicrobial peptides important in innate defense

Comparison of different sloshing speedmeters

By numerical simulation, we compare the performance of four speedmeter interferometer configurations with potential application in future gravitational wave detectors. In the absence of optical loss, all four configurations can be adjusted to yield the same sensitivity in a fair comparison. Once we introduce a degree of practicality in the form of lossy optics and mode mismatch, however, the situation changes: the sloshing Sagnac and the speedmeter of Purdue and Chen have almost identical performance showing smaller degradation from the ideal than the speedmeter of Freise and the speedmeter of Miao. In a further step, we show that there is a similar hierarchy in the degree of improvement obtained through the application of 10 dB squeezing to the lossy speedmeters. In this case, the sensitivity of each speedmeter improves, but it is greatest for the sloshing Sagnac and the speedmeter of Purdue and Chen, in particular in the lower part of the target frequency range

Use of Di(2-ethylhexyl) Phthalate–Containing Medical Products and Urinary Levels of Mono(2-ethylhexyl) Phthalate in Neonatal Intensive Care Unit Infants

Objective: Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in medical products made with polyvinyl chloride (PVC) plastic and may be toxic to humans. DEHP is lipophilic and binds non-covalently to PVC, allowing it to leach from these products. Medical devices containing DEHP are used extensively in neonatal intensive care units (NICUs). Among neonates in NICUs, we studied exposure to DEHP-containing medical devices in relation to urinary levels of mono(2-ethylhexyl) phthalate (MEHP), a metabolite of DEHP. Design: We used a cross-sectional design for this study. Participants: We studied 54 neonates admitted to either of two level III hospital NICUs for at least 3 days between 1 March and 30 April 2003. Measurements: A priori, we classified the infants’ exposures to DEHP based on medical products used: The low-DEHP exposure group included infants receiving primarily bottle and/or gavage feedings; the medium exposure group included infants receiving enteral feedings, intravenous hyperalimentation, and/or nasal continuous positive airway pressure; and the high exposure group included infants receiving umbilical vessel catheterization, endotracheal intubation, intravenous hyperalimentation, and indwelling gavage tube. We measured MEHP in the infants’ urine using automated solid-phase extraction/isotope dilution/high-performance liquid chromatography/ tandem mass spectrometry. Results: Urinary MEHP levels increased monotonically with DEHP exposure. For the low-, medium-, and high-DEHP exposure groups, median (interquartile range) MEHP levels were 4 (18), 28 (58), and 86 ng/mL (150), respectively (p = 0.004). After adjustment for institution and sex, urinary MEHP levels among infants in the high exposure group were 5.1 times those among infants in the low exposure group (p = 0.03). Conclusion: Intensive use of DEHP-containing medical devices in NICU infants results in higher exposure to DEHP as reflected by elevated urinary levels of MEHP

Towards Precision Medicine: Therapeutic Drug Monitoring–Guided Dosing of Vancomycin and β-lactam Antibiotics to Maximize Effectiveness and Minimize Toxicity

Purpose The goal of this review is to explore the role of antimicrobial therapeutic drug monitoring (TDM), especially in critically ill, obese, and older adults, with a specific focus on β-lactams and vancomycin. Summary The continued rise of antimicrobial resistance prompts the need to optimize antimicrobial dosing. The aim of TDM is to individualize antimicrobial dosing to achieve antibiotic exposures associated with improved patient outcomes. Initially, TDM was developed to minimize adverse effects during use of narrow therapeutic index agents. Today, patient and organism complexity are expanding the need for precision dosing through TDM services. Alterations of pharmacokinetics and pharmacodynamics (PK/PD) in the critically ill, obese, and older adult populations, in conjunction with declining organism susceptibility, complicate attainment of therapeutic targets. Over the last decade, antimicrobial TDM has expanded with the emergence of literature supporting β-lactam TDM and a shift from monitoring vancomycin trough concentrations to monitoring of the ratio of area under the concentration (AUC) curve to minimum inhibitory concentration (MIC). PK/PD experts should be at the forefront of implementing precision dosing practices. Conclusion Precision dosing through TDM is expanding and is especially important in populations with altered PK/PD, including critically ill, obese, and older adults. Due to wide PK/PD variability in these populations, TDM is vital to maximize antimicrobial effectiveness and decrease adverse event rates. However, there is still a need for studies connecting TDM to patient outcomes. Providing patient-specific care through β-lactam TDM and transitioning to vancomycin AUC/MIC monitoring may be challenging, but with experts at the forefront of this initiative, PK-based optimization of antimicrobial therapy can be achieved

Local-Oscillator Noise Coupling in Balanced Homodyne Readout for Advanced Gravitational Wave Detectors

The second generation of interferometric gravitational wave detectors are quickly approaching their design sensitivity. For the first time these detectors will become limited by quantum back-action noise. Several back-action evasion techniques have been proposed to further increase the detector sensitivity. Since most proposals rely on a flexible readout of the full amplitude- and phase-quadrature space of the output light field, balanced homodyne detection is generally expected to replace the currently used DC readout. Up to now, little investigation has been undertaken into how balanced homodyne detection can be successfully transferred from its ubiquitous application in table-top quantum optics experiments to large-scale interferometers with suspended optics. Here we derive implementation requirements with respect to local oscillator noise couplings and highlight potential issues with the example of the Glasgow Sagnac Speed Meter experiment, as well as for a future upgrade to the Advanced LIGO detectors.Comment: 7 pages, 5 figure

Effects of static and dynamic higher-order optical modes in balanced homodyne readout for future gravitational waves detectors

With the recent detection of Gravitational waves (GW), marking the start of the new field of GW astronomy, the push for building more sensitive laser-interferometric gravitational wave detectors (GWD) has never been stronger. Balanced homodyne detection (BHD) allows for a quantum noise (QN) limited readout of arbitrary light field quadratures, and has therefore been suggested as a vital building block for upgrades to Advanced LIGO and third generation observatories. In terms of the practical implementation of BHD, we develop a full framework for analyzing the static optical high order modes (HOMs) occurring in the BHD paths related to the misalignment or mode matching at the input and output ports of the laser interferometer. We find the effects of HOMs on the quantum noise limited sensitivity is independent of the actual interferometer configuration, e.g. Michelson and Sagnac interferometers are effected in the same way. We show that misalignment of the output ports of the interferometer (output misalignment) only effects the high frequency part of the quantum noise limited sensitivity (detection noise). However, at low frequencies, HOMs reduce the interferometer response and the radiation pressure noise (back action noise) by the same amount and hence the quantum noise limited sensitivity is not negatively effected in that frequency range. We show that the misalignment of laser into the interferometer (input misalignment) produces the same effect as output misalignment and additionally decreases the power inside the interferometer. We also analyze dynamic HOM effects, such as beam jitter created by the suspended mirrors of the BHD. Our analyses can be directly applied to any BHD implementation in a future GWD. Moreover, we apply our analytical techniques to the example of the speed meter proof of concept experiment under construction in Glasgow. We find that for our experimental parameters, the performance of our seismic isolation system in the BHD paths is compatible with the design sensitivity of the experiment

Demonstration of a switchable damping system to allow low-noise operation of high-Q low-mass suspension systems

Low mass suspension systems with high-Q pendulum stages are used to enable quantum radiation pressure noise limited experiments. Utilising multiple pendulum stages with vertical blade springs and materials with high quality factors provides attenuation of seismic and thermal noise, however damping of these high-Q pendulum systems in multiple degrees of freedom is essential for practical implementation. Viscous damping such as eddy-current damping can be employed but introduces displacement noise from force noise due to thermal fluctuations in the damping system. In this paper we demonstrate a passive damping system with adjustable damping strength as a solution for this problem that can be used for low mass suspension systems without adding additional displacement noise in science mode. We show a reduction of the damping factor by a factor of 8 on a test suspension and provide a general optimisation for this system.Comment: 5 pages, 5 figure

Ectodysplasin A Pathway Contributes to Human and Murine Skin Repair

The highly conserved ectodysplasin A (EDA)/EDA receptor signaling pathway is critical during development for the formation of skin appendages. Mutations in genes encoding components of the EDA pathway disrupt normal appendage development, leading to the human disorder hypohidrotic ectodermal dysplasia. Spontaneous mutations in the murine Eda (Tabby) phenocopy human X-linked hypohidrotic ectodermal dysplasia. Little is known about the role of EDA signaling in adult skin homeostasis or repair. Because wound healing largely mimics the morphogenic events that occur during development, we propose a role for EDA signaling in adult wound repair. Here we report a pronounced delay in healing in Tabby mice, demonstrating a functional role for EDA signaling in adult skin. Moreover, pharmacological activation of the EDA pathway in both Tabby and wild-type mice significantly accelerates healing, influencing multiple processes including re-epithelialization and granulation tissue matrix deposition. Finally, we show that the healing promoting effects of EDA receptor activation are conserved in human skin repair. Thus, targeted manipulation of the EDA/EDA receptor pathway has clear therapeutic potential for the future treatment of human pathological wound healing