Nanoscale mosaicity revealed in peptide microcrystals by scanning electron nanodiffraction.

Changes in lattice structure across sub-regions of protein crystals are challenging to assess when relying on whole crystal measurements. Because of this difficulty, macromolecular structure determination from protein micro and nanocrystals requires assumptions of bulk crystallinity and domain block substructure. Here we map lattice structure across micron size areas of cryogenically preserved three-dimensional peptide crystals using a nano-focused electron beam. This approach produces diffraction from as few as 1500 molecules in a crystal, is sensitive to crystal thickness and three-dimensional lattice orientation. Real-space maps reconstructed from unsupervised classification of diffraction patterns across a crystal reveal regions of crystal order/disorder and three-dimensional lattice tilts on the sub-100nm scale. The nanoscale lattice reorientation observed in the micron-sized peptide crystal lattices studied here provides a direct view of their plasticity. Knowledge of these features facilitates an improved understanding of peptide assemblies that could aid in the determination of structures from nano- and microcrystals by single or serial crystal electron diffraction

Effect of afterload alterations on the functional border zone measured with two-dimensional echocardiography during acute coronary occlusion

In the setting of acute myocardial infarction, pharmacologic intervention resulting in afterload changes are common but the effect of these changes on regional left ventricular function, and specifically the functional border zone, has not been fully investigated. Accordingly, we studied the effects of afterload manipulation on circumferential flow-function relationships and the functional border zone in 16 open-chest, anesthetized dogs. During left circumflex coronary artery occlusion, eight animals were infused with phenylephrine to increase afterload; eight others received nitroprusside for afterload reduction. Following coronary artery occlusion, subendocardial blood flow and wall thickening decreased in the ischemic zone (p p = ns). Similarly, when blood pressure was increased by 47%, the extent of the functional border zone did not change (32 +/- 10 degrees vs 37 +/- 10 degrees). Therefore circumferential flow-function relations and the spatial extent of the functional border zone are not altered by changing afterload during acute left circumflex coronary artery occlusion in this model.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27132/1/0000125.pd

An Investigation of the Ionic Conductivity and Species Crossover of Lithiated Nafion 117 in Nonaqueous Electrolytes

Nonaqueous redox flow batteries are a fast-growing area of research and development motivated by the need to develop low-cost energy storage systems. The identification of a highly conductive, yet selective membrane, is of paramount importance to enabling such a technology. Herein, we report the swelling behavior, ionic conductivity, and species crossover of lithiated Nafion 117 membranes immersed in three nonaqueous electrolytes (PC, PC : EC, and DMSO). Our results show that solvent volume fraction within the membrane has the greatest effect on both conductivity and crossover. An approximate linear relationship between diffusive crossover of neutral redox species (ferrocene) and the ionic conductivity of membrane was observed. As a secondary effect, the charge on redox species modifies crossover rates in accordance with Donnan exclusion. The selectivity of membrane is derived mathematically and compared to experimental results reported here. The relatively low selectivity for lithiated Nafion 117 in nonaqueous conditions suggests that new membranes are required for competitive nonaqueous redox flow batteries to be realized. Potential design rules are suggested for the future membrane engineering work.United States. Dept. of Energy. Office of Basic Energy Sciences. Joint Center for Energy Storage Researc

Aging modulates the effects of ischemic injury upon mesenchymal cells within the renal interstitium and microvasculature

Abstract The renal mesenchyme contains heterogeneous cells, including interstitial fibroblasts and pericytes, with key roles in wound healing. Although healing is impaired in aged kidneys, the effect of age and injury on the mesenchyme remains poorly understood. We characterized renal mesenchymal cell heterogeneity in young vs old animals and after ischemia‐reperfusion‐injury (IRI) using multiplex immunolabeling and single cell transcriptomics. Expression patterns of perivascular cell markers (α‐SMA, CD146, NG2, PDGFR‐α, and PDGFR‐β) correlated with their interstitial location. PDGFR‐α and PDGFR‐β co‐expression labeled renal myofibroblasts more efficiently than the current standard marker α‐SMA, and CD146 was a superior murine renal pericyte marker. Three renal mesenchymal subtypes; pericytes, fibroblasts, and myofibroblasts, were recapitulated with data from two independently performed single cell transcriptomic analyzes of murine kidneys, the first dataset an aging cohort and the second dataset injured kidneys following IRI. Mesenchymal cells segregated into subtypes with distinct patterns of expression with aging and following injury. Baseline uninjured old kidneys resembled post‐ischemic young kidneys, with this phenotype further exaggerated following IRI. These studies demonstrate that age modulates renal perivascular/interstitial cell marker expression and transcriptome at baseline and in response to injury and provide tools for the histological and transcriptomic analysis of renal mesenchymal cells, paving the way for more accurate classification of renal mesenchymal cell heterogeneity and identification of age‐specific pathways and targets

Effects of fasting on serial measurements of hyperpolarized [1-(13) C]pyruvate metabolism in tumors.

Imaging of the metabolism of hyperpolarized [1-(13) C]pyruvate has shown considerable promise in preclinical studies in oncology, particularly for the assessment of early treatment response. The repeatability of measurements of (13) C label exchange between pyruvate and lactate was determined in a murine lymphoma model in fasted and non-fasted animals. The fasted state showed lower intra-individual variability, although the [1-(13) C]lactate/[1-(13) C]pyruvate signal ratio was significantly greater in fasted than in non-fasted mice, which may be explained by the higher tumor lactate concentrations in fasted animals. These results indicate that the fasted state may be preferable for the measurement of (13) C label exchange between pyruvate and lactate, as it reduces the variability and therefore should make it easier to detect the effects of therapy. © 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.Cancer Research UK (Grant ID: 17242)This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1002/nbm.356

In-hospital adverse drug reactions in hospitalised older adults - a systematic review

Introduction: Studies indicate 1 in 4 older people experience hospital-related adverse drug reactions [ADRs]. This systematic-review aims to evaluate in-hospital ADRs in hospitalised older-adults in terms of incidence, prevalence, most commonly involved drug classes, severity, and consequences. Methods: Using PRISMA methodology [PROSPERO CRD42018079095], we searched PubMed, Embase, Ebsco-CINAHL, Cochrane Library, library hosted sources, Google scholar, and ‘grey’ literature, using terms; aged, ADRs, hospitalized, multi-morbid, polypharmacy and hospital-acquired. References of editorials and systematic reviews were hand searched. Studies of all languages and dates until 15/01/2018 were included. All studies reporting ADRs outcomes, ≥65 years, hospitalised at time of ADR occurrence were included. Two researchers screened all papers for inclusion, risk of bias and data extraction. Results: Initial search yielded 1721 abstracts, 200 underwent full text screening. 60 were potentially suitable for inclusion; 48 papers reported combined ages, 12 papers reported directly on ADRs in our age cohort [2 papers reported the same data]. 11 studies [4424 patients] were analysed; 24% [1064] experienced ADRs. 7 reported severity (n = 707); 31% [220] being severe. 5 reported on post-ADR outcomes i.e. length of stay [n = 3], death [n = 1] and functional decline [n = 1]. Frequency of culprit drug-groups were described in 6 [672 ADRs]; 43% [291] cardiovascular system, 17% [114] central nervous system, 16% [112] clotting pathways, 13% [90] anti-microbials. Conclusions: One in four over 65 years experience an ADR during hospitalisation, one third being severe, and almost half cardiovascular system drugs. Clinical outcomes associated with ADRs are generally poorly described in the literature.Poster presentatio

Long term abundance patterns of potamodromous brown trout in a large lacustrine catchment in County Fermanagh

Publication history: Accepted - 12 February 2021; Published online - 29 September 2021.Long-term survey data detailing brown trout abundance in the Lough Erne catchment in Co. Fermanagh were tabulated from 1968–2016. These data included redd counts and electric fishing surveys across three key spawning tributaries in addition to gill-net surveys of the lake. The abundance of spawning adults fluctuated widely across the time-series and were examined in relation to various pressures, including a major disease epidemic and the invasion of the catchment by zebra mussels. A functional stock-recruitment relationship between adult spawners and young-of-year juveniles in the spawning tributaries was identified and described. Redd counts were significantly lower for the post-zebra mussel time-series (2000–16) than the pre-zebra mussel time-series (1968–99). The post-zebra mussel invasion period was associated with increased water clarity, reduced plankton productivity and changes to the balance of coarse fish species in the lake. The significance of these changes is discussed in relation to the trout stock

A comparison of quantitative methods for clinical imaging with hyperpolarized (13)C-pyruvate.

Dissolution dynamic nuclear polarization (DNP) enables the metabolism of hyperpolarized (13)C-labelled molecules, such as the conversion of [1-(13)C]pyruvate to [1-(13)C]lactate, to be dynamically and non-invasively imaged in tissue. Imaging of this exchange reaction in animal models has been shown to detect early treatment response and correlate with tumour grade. The first human DNP study has recently been completed, and, for widespread clinical translation, simple and reliable methods are necessary to accurately probe the reaction in patients. However, there is currently no consensus on the most appropriate method to quantify this exchange reaction. In this study, an in vitro system was used to compare several kinetic models, as well as simple model-free methods. Experiments were performed using a clinical hyperpolarizer, a human 3 T MR system, and spectroscopic imaging sequences. The quantitative methods were compared in vivo by using subcutaneous breast tumours in rats to examine the effect of pyruvate inflow. The two-way kinetic model was the most accurate method for characterizing the exchange reaction in vitro, and the incorporation of a Heaviside step inflow profile was best able to describe the in vivo data. The lactate time-to-peak and the lactate-to-pyruvate area under the curve ratio were simple model-free approaches that accurately represented the full reaction, with the time-to-peak method performing indistinguishably from the best kinetic model. Finally, extracting data from a single pixel was a robust and reliable surrogate of the whole region of interest. This work has identified appropriate quantitative methods for future work in the analysis of human hyperpolarized (13)C data.CJD is jointly funded by the National Institute for Health Research (NIHR), Cambridge Biomedical Research Centre and GlaxoSmithKline (GSK). Additional funding for this study was provided by Cancer Research UK (CRUK, C19212/A16628; C19212/A911376), The Wellcome Trust, Cambridge Experimental Cancer Medicine Centre, Cambridge Cancer Centre, the School of Clinical Medicine at the University of Cambridge and the CRUK and Engineering and Physical Sciences Research Council (EPSRC) Cancer Imaging Centre in Cambridge and Manchester.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/nbm.346

JWST mirror and actuator performance at cryo-vacuum

The James Webb Space Telescope (JWST) telescope’s Secondary Mirror Assembly (SMA) and eighteen Primary Mirror Segment Assemblies (PMSAs) are each actively controlled in rigid body position via six hexapod actuators. Each of the PMSAs additionally has a radius of curvature actuator. The mirrors are stowed to the mirror support structure to survive the launch environment and then must be deployed 12.5 mm to reach the nominally deployed position before the Wavefront Sensing & Control (WFSC) alignment and phasing process begins. JWST requires testing of the full optical system in a Cryogenic Vacuum (CV) environment before launch. The cryo vacuum test campaign was executed in Chamber A at the Johnson Space Center (JSC) in Houston Texas. The test campaign consisted of an ambient vacuum test, a cooldown test, a cryo stable test at 65 Kelvin, a warmup test, and finally a second ambient vacuum test. Part of that test campaign was the functional and performance testing of the hexapod actuators on the flight mirrors. This paper will describe the testing that was performed on all 132 hexapod and radius of curvature actuators. The test campaign first tests actuators individually then tested how the actuators perform in the hexapod system. Telemetry from flight sensors on the actuators and measurements from external metrology devices such as interferometers, photogrammetry systems and image analysis was used to demonstrate the performance of the JWST actuators. The mirror move commanding process was exercised extensively during the JSC CV test and many examples of accurately commanded moves occurred. The PMSA and SMA actuators performed extremely well during the JSC CV test, and we have demonstrated that the actuators are fully functional both at ambient and cryo temperatures and that the mirrors will go to their commanded positions with the accuracy needed to phase and align the telescope

Improving guideline adherence in urology

Dr. Skolarus is supported by the National Cancer Institute R01 CA242559 and R37 CA222885. No conflicts of interest.Peer reviewedPostprin