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1.  Discovery of FeBi2 
ACS Central Science  2016;2(11):867-871.
Recent advances in high-pressure techniques offer chemists access to vast regions of uncharted synthetic phase space, expanding our experimental reach to pressures comparable to the core of the Earth. These newfound capabilities enable us to revisit simple binary systems in search of compounds that for decades have remained elusive. The most tantalizing of these targets are systems in which the two elements in question do not interact even as molten liquids—so-called immiscible systems. As a prominent example, immiscibility between iron and bismuth is so severe that no material containing Fe–Bi bonds is known to exist. The elusiveness of Fe–Bi bonds has a myriad of consequences; crucially, it precludes completing the iron pnictide superconductor series. Herein we report the first iron–bismuth binary compound, FeBi2, featuring the first Fe–Bi bond in the solid state. We employed geologically relevant pressures, similar to the core of Mars, to access FeBi2, which we synthesized at 30 GPa and 1500 K. The compound crystallizes in the Al2Cu structure type (space group I4/mcm) with a = 6.3121(3) Å and c = 5.4211(4) Å. The new binary intermetallic phase persists from its formation pressure of 30 GPa down to 3 GPa. The existence of this phase at low pressures suggests that it might be quenchable to ambient pressure at low temperatures. These results offer a pathway toward the realization of new exotic materials.
Harnessing pressures comparable to those found at the core of Mars, we synthesized the first iron−bismuth binary compound featuring the first iron−bismuth bond in a solid-state material.
doi:10.1021/acscentsci.6b00287
PMCID: PMC5126710  PMID: 27924316
2.  Effect of Scar Compaction on the Therapeutic Efficacy of Anisotropic Reinforcement Following Myocardial Infarction in the Dog 
Cardiac restraint devices have been used following myocardial infarction (MI) to limit left ventricular (LV) dilation, although isotropic restraints have not been shown to improve post-MI LV function. We have previously shown that anisotropic reinforcement of acute infarcts dramatically improves LV function. This study examined the effects of chronic, anisotropic infarct restraint on LV function and remodeling. Hemodynamics, infarct scar structure, and LV volumes were measured in 28 infarcted dogs (14 reinforced, 14 control). Longitudinal restraint reduced 48hr LV volumes, but no differences in LV volume, function, or infarct scar structure were observed after 8 weeks of healing. All scars underwent substantial compaction during healing; we hypothesize that compaction negated the effects of restraint therapy by mechanically unloading the restraint device. Our results lend support to the concept of adjustable restraint devices, and suggest that scar compaction may explain some of the variability in published studies of local infarct restraint.
doi:10.1007/s12265-015-9637-1
PMCID: PMC4527936  PMID: 26077797
myocardial infarction; infarct restraint; scar compaction; left ventricular remodeling
3.  Impact of Mechanical Activation, Scar, and Electrical Timing on Cardiac Resynchronization Therapy Response and Clinical Outcomes 
Objectives
Using cardiac magnetic resonance (CMR), we sought to evaluate the relative influences of mechanical, electrical, and scar properties at the left ventricular (LV) lead position (LVLP) on CRT response and clinical events.
Background
CMR cine displacement encoding with stimulated echoes (DENSE) provides high quality strain for overall dyssynchrony (circumferential uniformity ratio estimate [CURE, 0–1]) and timing of onset of circumferential contraction at the LVLP. CMR DENSE, late gadolinium enhancement, and electrical timing together could improve upon other imaging modalities for evaluating the optimal LVLP.
Methods
Patients had complete CMR studies and echocardiography before CRT. CRT response was defined as a 15% reduction in LV end-systolic volume. Electrical activation was assessed as the time from QRS-onset-to-LVLP-electrogram (QLV). Patients were then followed for clinical events.
Results
In 75 patients, multivariable logistic modeling accurately identified the 40 (53%) of patients with CRT response (AUC=0.95 [p<0.0001]) based on CURE (OR 2.59/0.1 decrease), delayed circumferential contraction onset at LVLP (OR 6.55), absent LVLP scar (OR 14.9), and QLV (OR 1.31/10 ms increase). The 33% of patients with CURE<0.70, absence of LVLP scar, and delayed LVLP contraction onset had a 100% response rate, whereas those with CURE≥0.70 had a 0% CRT response rate and a 12-fold increased risk of death, and the remaining patients had a mixed response profile.
Conclusions
Mechanical, electrical, and scar properties at the LVLP together with CMR mechanical dyssynchrony are strongly associated with echocardiographic CRT response and clinical events after CRT. Modeling these findings holds promise for improving CRT outcomes.
doi:10.1016/j.jacc.2014.02.533
PMCID: PMC4427624  PMID: 24583155
cardiac resynchronization therapy; cardiac magnetic resonance; heart failure; myocardial infarction; ventricular tachycardia
4.  A Novel Electronic Assessment Strategy to Support Applied Drosophila Genetics Training in University Courses 
G3: Genes|Genomes|Genetics  2015;5(5):689-698.
The advent of “omic” technologies has revolutionized genetics and created a demand to focus classical genetics on its present-day applications (Redfield, 2012, PLoS Biol 10: e1001356). This demand can be met by training students in Drosophila mating scheme design, which is an important problem-solving skill routinely applied in many modern research laboratories. It promotes a thorough understanding and application of classical genetics rules and introduces to transgenic technologies and the use of model organisms. As we show here, such training can be implemented as a flexible and concise module (~1-day home study, ~8-hour course time) on university courses by using our previously published training package designed for fly researchers (Roote and Prokop, 2013, G3 (Bethesda) 3: 353−358). However, assessing this training to make it an accredited course element is difficult, especially in large courses. Here, we present a powerful assessment strategy based on a novel hybrid concept in which students solve crossing tasks initially on paper and then answer automatically marked questions on the computer (1.5 hours total). This procedure can be used to examine student performance on more complex tasks than conventional e-assessments and is more versatile, time-saving, and fairer than standard paper-based assignments. Our evaluation shows that the hybrid assessment is effective and reliably detects varying degrees of understanding among students. It also may be applicable in other disciplines requiring complex problem solving, such as mathematics, chemistry, physics, or informatics. Here, we describe our strategies in detail and provide all resources needed for their implementation.
doi:10.1534/g3.115.017509
PMCID: PMC4426358  PMID: 25717150
Drosophila; genetics; university; teaching; electronic assessment
5.  Postprocedure Mapping of Cardiac Resynchronization Lead Position Using Standard Fluoroscopy Systems: Implications for the Nonresponder with Scar 
Background
The relationship between cardiac resynchronization therapy (CRT), left ventricular (LV) lead position, scar, and regional mechanical function influences CRT response.
Objective
To determine LV lead position relative to LV structural characteristics in standard clinical practice, we developed and validated a practical yet mathematically rigorous method to register procedural fluoroscopic LV lead position with pre-CRT cardiac magnetic resonance (CMR).
Methods
After one-time calibration of the standard fluoroscopic suite, we identified the projected CMR LV lead position using three reference landmarks on both CMR and fluoroscopy. This predicted lead position was validated in a canine model by histology and in eight “validation group” patients based on postoperative computed tomography scans (n = 7) or CMR coronary sinus venography (n = 1). The methodology was applied in an additional eight patients with CRT nonresponse and infarction-related myocardial scar.
Results
The projected and actual lead positions were within 1.2 mm in the canine model. The median distance between projected and actual lead positions for the validation group (n = 8) and animal validation case was 11.3 mm (interquartile range 9.2–14.6 mm). In the application (nonresponder) group (n = 8), the lead mapped to the scar periphery in three patients, the core of the scar in one patient, and more than 3 cm from scar in four patients.
Conclusions
This methodology projects procedural fluoroscopic LV lead position onto pre-CRT CMR using standard fluoroscopic equipment and a one-time calibration, enabling assessment of LV lead position with sufficient accuracy to identify the lead position relative to regional function and infarction-related scar in CRT nonresponders.
doi:10.1111/pace.12344
PMCID: PMC4055519  PMID: 24472061
cardiac resynchronization therapy; devices for heart failure; cardiac magnetic resonance; fluoroscopy; coronary sinus; biomedical engineering; myocardial infarction
7.  Inhibition of mitochondrial permeability transition pore opening by ischemic preconditioning is probably mediated by reduction of oxidative stress rather than mitochondrial protein phosphorylation 
Circulation research  2008;102(9):1082-1090.
Inhibition of mitochondrial permeability transition pore (MPTP) opening at reperfusion is critical for cardioprotection by ischemic preconditioning (IP). Some studies have implicated mitochondrial protein phosphorylation in this effect. Here we confirm that mitochondria rapidly isolated from pre-ischemic control and IP-hearts show no significant difference in calcium-mediated MPTP opening, whereas IP inhibits MPTP opening in mitochondria isolated from IP-hearts following 30 min global normothermic ischemia or 3 min reperfusion. Analysis of protein phosphorylation in density-gradient purified mitochondria was performed using both 2D and 1D electrophoresis with detection of phosphoproteins using Pro-Q Diamond or phospho-amino specific antibodies. Several phosphoproteins were detected, including voltage-dependent anion channels isoforms 1 and 2, but none showed significant IP-mediated changes either before ischemia or during ischemia and reperfusion. Nor did either Western blotting or 2-D fluorescence difference gel electrophoresis (DIGE) detect translocation of protein kinase C (α, ε or δ isoforms), glycogen synthase kinase 3β (GSK3β), or Akt to the mitochondria following IP. In freeze-clamped hearts changes in phosphorylation of GSK3β, Akt and AMP-activated protein kinase (AMPK) were detected following ischemia and reperfusion but no IP-mediated changes correlated with MPTP inhibition or cardioprotection. However, measurement of mitochondrial protein carbonylation, a surrogate marker for oxidative stress, suggested that a reduction in mitochondrial oxidative stress at the end of ischemia and during reperfusion might account for IP-mediated inhibition of MPTP. The signalling pathways mediating this effect and maintaining it during reperfusion are discussed.
doi:10.1161/CIRCRESAHA.107.167072
PMCID: PMC2629616  PMID: 18356542
Mitochondrial permeability transition; preconditioning; reperfusion injury; protein phosphorylation; oxidative stress
8.  Routine care of peripheral intravenous catheters versus clinically indicated replacement: randomised controlled trial 
BMJ : British Medical Journal  2008;337(7662):157-160.
Objective To compare routine replacement of intravenous peripheral catheters with replacement only when clinically indicated.
Design Randomised controlled trial.
Setting Tertiary hospital in Australia.
Participants 755 medical and surgical patients: 379 allocated to catheter replacement only when clinically indicated and 376 allocated to routine care of catheter (control group).
Main outcome measure A composite measure of catheter failure resulting from phlebitis or infiltration.
Results Catheters were removed because of phlebitis or infiltration from 123 of 376 (33%) patients in the control group compared with 143 of 379 (38%) patients in the intervention group; the difference was not significant (relative risk 1.15, 95% confidence interval 0.95 to 1.40). When the analysis was based on failure per 1000 device days (number of failures divided by number of days catheterised, divided by 1000), no difference could be detected between the groups (relative risk 0.98, 0.78 to 1.24). Infusion related costs were higher in the control group (mean $A41.02; £19.71; €24.80; $38.55) than intervention group ($A36.40). The rate of phlebitis in both groups was low (4% in intervention group, 3% in control group).
Conclusion Replacing peripheral intravenous catheters when clinically indicated has no effect on the incidence of failure, based on a composite measure of phlebitis or infiltration. Larger trials are needed to test this finding using phlebitis alone as a more clinically meaningful outcome.
Registration number Australian New Zealand Clinical Trials Registry ACTRN12605000147684.
doi:10.1136/bmj.a339
PMCID: PMC2483870  PMID: 18614482
9.  Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly, by reducing oxidative stress 
Urocortin (Ucn) protects hearts against ischemia and reperfusion injury whether given prior to ischemia or at reperfusion. Here we investigate the roles of protein kinase C, reactive oxygen species, and the mitochondrial permeability transition pore (MPTP) in mediating these effects. In Langendorff-perfused rat hearts, acute Ucn treatment improved hemodynamic recovery during reperfusion after 30 min global ischemia; this was accompanied by less necrosis (lactate dehydrogenase release) and MPTP opening (mitochondrial entrapment of [3H]-2-deoxyglucose). Ucn pre-treatment protected mitochondria against calcium-induced MPTP opening, but only if the mitochondria had been isolated from hearts after reperfusion. These mitochondria also exhibited less protein carbonylation, suggesting that Ucn decreases levels of oxidative stress. In isolated adult and neonatal rat cardiac myocytes, both acute (60 min) and chronic (16 hr) treatment with Ucn reduced cell death following simulated ischemia and re-oxygenation. This was accompanied by less MPTP opening as measured using tetramethylrhodamine methyl ester. The level of oxidative stress during reperfusion was reduced in cells which had been pre-treated with Ucn suggesting that this is the mechanism by which Ucn desensitizes the MPTP to reperfusion injury. Despite the fact that we could find no evidence that either PKCε or PKCα translocate to the mitochondria following acute Ucn treatment, inhibition of PKC with chelerythrine eliminated the effect of Ucn on oxidative stress. Our data suggests that acute Ucn treatment protects the heart by inhibiting MPTP opening. However, the mechanism appears to be indirect, involving a PKC-mediated reduction in oxidative stress.
doi:10.1152/ajpheart.01135.2006
PMCID: PMC1950441  PMID: 17483234
reperfusion; mitochondria; oxygen radicals; peptide hormones
10.  Routine care of peripheral intravenous catheters versus clinically indicated replacement: randomised controlled trial 
Objective To compare routine replacement of intravenous peripheral catheters with replacement only when clinically indicated.
Design Randomised controlled trial.
Setting Tertiary hospital in Australia.
Participants 755 medical and surgical patients: 379 allocated to catheter replacement only when clinically indicated and 376 allocated to routine care of catheter (control group).
Main outcome measure A composite measure of catheter failure resulting from phlebitis or infiltration.
Results Catheters were removed because of phlebitis or infiltration from 123 of 376 (33%) patients in the control group compared with 143 of 379 (38%) patients in the intervention group; the difference was not significant (relative risk 1.15, 95% confidence interval 0.95 to 1.40). When the analysis was based on failure per 1000 device days (number of failures divided by number of days catheterised, divided by 1000), no difference could be detected between the groups (relative risk 0.98, 0.78 to 1.24). Infusion related costs were higher in the control group (mean $A41.02; £19.71; €24.80; $38.55) than intervention group ($A36.40). The rate of phlebitis in both groups was low (4% in intervention group, 3% in control group).
Conclusion Replacing peripheral intravenous catheters when clinically indicated has no effect on the incidence of failure, based on a composite measure of phlebitis or infiltration. Larger trials are needed to test this finding using phlebitis alone as a more clinically meaningful outcome.
Registration number Australian New Zealand Clinical Trials Registry ACTRN12605000147684.
doi:10.1136/bmj.a339
PMCID: PMC2483870  PMID: 18614482
11.  The role of mitochondria in protection of the heart by preconditioning 
Biochimica et Biophysica Acta  2007;1767(8):1007-1031.
A prolonged period of ischaemia followed by reperfusion irreversibly damages the heart. Such reperfusion injury (RI) involves opening of the mitochondrial permeability transition pore (MPTP) under the conditions of calcium overload and oxidative stress that accompany reperfusion. Protection from MPTP opening and hence RI can be mediated by ischaemic preconditioning (IP) where the prolonged ischaemic period is preceded by one or more brief (2–5 min) cycles of ischaemia and reperfusion. Following a brief overview of the molecular characterisation and regulation of the MPTP, the proposed mechanisms by which IP reduces pore opening are reviewed including the potential roles for reactive oxygen species (ROS), protein kinase cascades, and mitochondrial potassium channels. It is proposed that IP-mediated inhibition of MPTP opening at reperfusion does not involve direct phosphorylation of mitochondrial proteins, but rather reflects diminished oxidative stress during prolonged ischaemia and reperfusion. This causes less oxidation of critical thiol groups on the MPTP that are known to sensitise pore opening to calcium. The mechanisms by which ROS levels are decreased in the IP hearts during prolonged ischaemia and reperfusion are not known, but appear to require activation of protein kinase Cε, either by receptor-mediated events or through transient increases in ROS during the IP protocol. Other signalling pathways may show cross-talk with this primary mechanism, but we suggest that a role for mitochondrial potassium channels is unlikely. The evidence for their activity in isolated mitochondria and cardiac myocytes is reviewed and the lack of specificity of the pharmacological agents used to implicate them in IP is noted. Some K+ channel openers uncouple mitochondria and others inhibit respiratory chain complexes, and their ability to produce ROS and precondition hearts is mimicked by bona fide uncouplers and respiratory chain inhibitors. IP may also provide continuing protection during reperfusion by preventing a cascade of MPTP-induced ROS production followed by further MPTP opening. This phase of protection may involve survival kinase pathways such as Akt and glycogen synthase kinase 3 (GSK3) either increasing ROS removal or reducing mitochondrial ROS production.
doi:10.1016/j.bbabio.2007.05.008
PMCID: PMC2212780  PMID: 17631856
5HD, 5-hydroxydecanoate; AMPK, AMP activated protein kinase; ANT, Adenine nucleotide translocase; APD, Action potential duration; BCDH, branched chain 2-oxoacid dehydrogenase; CrK, creatine kinase; CsA, cyclosporin A; CyP, cyclophilin; Cx43, connexin43; GSK3, glycogen synthase kinase 3; IP, ischaemic preconditioning; KATP, ATP-dependent potassium channels; mitoKATP, mitochondrial ATP-dependent potassium channels; MCT1, monocarboxylate transporter 1; MPTP, mitochondrial permeability transition pore; PDH, pyruvate dehydrogenase; PDK1, phosphoinositide-dependent kinase 1; PI-3-kinase, phosphatidyl inositol 3 phosphate kinase; PKC, protein kinase C; PKG, cyclic GMP-dependent protein kinase; PPi, pyrophosphate; PPIase, peptidyl-prolyl cis-trans isomerase; PTEN, Phosphatase and TENsin homolog; ROS, reactive oxygen species; SfA, Sanglifehrin A; SUR, sulphohylurea receptor; VDAC, voltage activated anion channel; Mitochondrial permeability transition pore; Ischaemia; Reperfusion; ROS; Calcium; PKC; KATP channel

Results 1-11 (11)