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Background/Objectives: Extracts of the plant Centella asiatica can enhance mitochondrial function, promote antioxidant activity and improve cognitive deficits. Asiatic acid (AA) is one of the constituent triterpene compounds present in the plant. In this study, we explore the effects of AA on brain mitochondrial function, antioxidant response and cognition in a beta-amyloid (Aβ)-overexpressing 5xFAD mouse line. Methods: Six- to seven-month-old 5xFAD mice were treated with 1% AA for 4 weeks. In the last week of treatment, associative memory was assessed along with mitochondrial bioenergetics and the expression of mitochondrial and antioxidant response genes from isolated cortical synaptosomes. The Aβ plaque burden was also evaluated. Results: AA treatment resulted in improvements in associative memory in female 5xFAD mice without altering the Aβ plaque burden. Cortical mitochondrial function and mitochondrial gene expression were increased in the AA-treated female 5xFAD mice, as was the expression of antioxidant genes. More modest effects of AA on cortical mitochondrial function and mitochondrial and antioxidant gene expression were observed in male 5xFAD mice. Conclusions: Oral AA treatment improved cognitive and mitochondrial function and activated antioxidant in Aβ-overexpressing mice. These changes occurred independent of alterations in Aβ plaque burden, suggesting that AA could have translational therapeutic relevance in later-stage AD when plaques are well established.

Extracts of the plant Centella asiatica can enhance mitochondrial function, promote antioxidant activity and improve cognitive deficits. Asiatic acid (AA) is one of the constituent triterpene compounds present in the plant. In this study we explore the effects of increasing concentrations of AA on brain mitochondrial function, antioxidant response and cognition in healthy mice and a single concentration of AA in the beta-amyloid overexpressing 5xFAD mouse line. Associative memory and overall activity were assessed. Hippocampal mitochondrial bioenergetics and the expression of mitochondrial and antioxidant response genes was determined. In the 5xFAD line, total beta-amyloid plaque burden after AA treatment was also evaluated. In healthy mice, we report dose responsive effects of increasing concentrations of AA on enhanced associative memory and a dose dependent increase in basal and maximal mitochondrial respiration, mitochondrial gene expression and antioxidant gene expression. Results from the highest AA dose (1% AA) were similar to what was observed with CAW. The high AA dose was then evaluated in the context of Aβ accumulation in 5xFAD mice. Improvements in mitochondrial and antioxidant response genes were favored in females over males without significant alleviation of Aβ plaque burden.Competing Interest StatementThe authors have declared no competing interest.

Coupling between the lower and upper atmosphere, combined with loss of gas from the upper atmosphere to space, likely contributed to the thin, cold, dry atmosphere of modern Mars. To help understand ongoing ion loss to space, the Mars Atmosphere and Volatile Evolution (MAVEN) spacecraft made comprehensive measurements of the Mars upper atmosphere, ionosphere, and interactions with the Sun and solar wind during an interplanetary coronal mass ejection impact in March 2015. Responses include changes in the bow shock and magnetosheath, formation of widespread diffuse aurora, and enhancement of pick-up ions. Observations and models both show an enhancement in escape rate of ions to space during the event. Ion loss during solar events early in Mars history may have been a major contributor to the long-term evolution of the Mars atmosphere.

The Mars Atmosphere and Volatile Evolution (MAVEN) mission, during the second of its Deep Dip campaigns, made comprehensive measurements of martian thermosphere and ionosphere composition, structure, and variability at altitudes down to ~130 kilometers in the subsolar region. This altitude range contains the diffusively separated upper atmosphere just above the well-mixed atmosphere, the layer of peak extreme ultraviolet heating and primary reservoir for atmospheric escape. In situ measurements of the upper atmosphere reveal previously unmeasured populations of neutral and charged particles, the homopause altitude at approximately 130 kilometers, and an unexpected level of variability both on an orbit-to-orbit basis and within individual orbits. These observations help constrain volatile escape processes controlled by thermosphere and ionosphere structure and variability.

Our goal was to determine if the hemolysis among blood samples obtained in an emergency department and then sent to the laboratory in a pneumatic tube system was different from those in samples that were hand-carried. The hemolysis index is measured on all samples submitted for potassium analysis. We queried our hospital laboratory database system (SunQuest(®)) for potassium results for specimens obtained between January 2014 and July 2014. From facility maintenance records, we identified periods of system downtime, during which specimens were hand-carried to the laboratory. During the study period, 15,851 blood specimens were transported via our pneumatic tube system and 92 samples were hand delivered. The proportions of hemolyzed specimens in the two groups were not significantly different (13.6% vs. 13.1% [p=0.90]). Results were consistent when the criterion was limited to gross (3.3% vs 3.3% [p=0.99]) or mild (10.3% vs 9.8% [p=0.88]) hemolysis. The hemolysis rate showed minimal variation during the study period (12.6%-14.6%). We found no statistical difference in the percentages of hemolyzed specimens transported by a pneumatic tube system or hand delivered to the laboratory. Certain features of pneumatic tube systems might contribute to hemolysis (e.g., speed, distance, packing material). Since each system is unique in design, we encourage medical facilities to consider whether their method of transport might contribute to hemolysis in samples obtained in the emergency department.

Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases. The X-ray structures reveal a binding site outside the kinase active site that uses residues from the kinase domain and the juxtamembrane region. Three modes of binding with the juxtamembrane region are characterized through a series of ligand-bound complexes. The structures indicate a critical pharmacophore on the compounds that leads to the distinct binding modes. The mode of interaction can allow TrkA selectivity over TrkB and TrkC or promiscuous, pan-Trk inhibition. This finding highlights the difficulty in characterizing the structure-activity relationship of a chemical series in the absence of structural information because of substantial differences in the interacting residues. These structures illustrate the flexibility of binding to sequences outside of—but adjacent to—the kinase domain of TrkA. This knowledge allows development of compounds with specificity for TrkA or the family of Trk proteins.

Standard procedures for using nuclear Overhauser enhancements (NOE) between protons to generate structures for diamagnetic proteins in solution from NMR data may be supplemented by using dipolar shifts if the protein is paramagnetic. This is advantageous since the electron -nuclear dipolar coupling provides relatively long-range geometric information with respect to the paramagnetic centre which complements the short-range distance constraints NOEs. Several different strategies have been developed to date, but none of these attempts to combine data from NOEs and dipolar shifts in the initial stages of structure calculation or to determine three dimensional protein structures together with their magnetic properties. This work shows that the magnetic and atomic structures are highly correlated and that it is important to have additional constraints both to provide starting parameters for the magnetic properties and to improve the definition of the best fit. Useful parameters can be obtained for haem proteins from Fermi contact shifts; this approach is compared with a new method based on the analysis of dipolar shifts in haem methyl groups with respect to data from horse and tuna ferricytochromes c. The methods developed for using data from NOEs and dipolar shifts have been incorporated in a new computer program, PARADYANA, which is demonstrated in application to a model data set for the sequence of the haem octapeptide known as microperoxidase-8.

Pseudomonas aeruginosa colonization and infection was studied over a 6-mo period in a 36-bed mixed general medical-oncology unit. Weused selective media for serial surveillance cultures on 283 patients, the environment, and personnel. Twelve percent of patients were colonized on admission and 10% acquired P. aeruginosa. Using serotyping and multilocus enzyme electrophoresis, we identified 63 genetically distinctive strains; four prevalent strains accounted for 21% of isolates. Only 5 of 33 nosocomial acquisitions were due to horizontal transmission. Nine acquisitions were linked to environmental sources (e.g., sink surfaces), which often harbored antibiotic-resistant strains but posed a risk only to oncology patients. Although significant Pseudomonas infections occurred in only 11% of colonized patients, 63% of colonized severely neutropenic patientsp — redominantly those who had acquired the prevalent, often environmentally linked strains — developed infections. Thus, P. aeruginosa was a significant pathogen in oncology patients; typing by multilocus enzyme electrophoresis allowed the detection of important environmental sources.

We present high-precision timing data over time spans of up to 11 years for 45 millisecond pulsars observed as part of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) project, aimed at detecting and characterizing low-frequency gravitational waves. The pulsars were observed with the Arecibo Observatory and/or the Green Bank Telescope at frequencies ranging from 327 MHz to 2.3 GHz. Most pulsars were observed with approximately monthly cadence, with six high--timing-precision pulsars observed weekly, and all were observed at widely separated frequencies at each observing epoch in order to fit for time-variable dispersion delays. We describe our methods for data processing, time-of-arrival (TOA) calculation, and the implementation of a new, automated method for removing outlier TOAs. We fit a timing model for each pulsar that includes spin, astrometric, and, if necessary, binary parameters, in addition to time-variable dispersion delays and parameters that quantify pulse-profile evolution with frequency. The new timing solutions provide three new parallax measurements, two new Shapiro delay measurements, and two new measurements of large orbital-period variations. We fit models that characterize sources of noise for each pulsar. We find that 11 pulsars show significant red noise, with generally smaller spectral indices than typically measured for non-recycled pulsars, possibly suggesting a different origin. Future papers will use these data to constrain or detect the signatures of gravitational-wave signals.