Interactions of the Gasotransmitters Contribute to Microvascular Tone (Dys)regulation in the Preterm Neonate

Background & Aims Hydrogen sulphide (H2S), nitric oxide (NO), and carbon monoxide (CO) are involved in transitional microvascular tone dysregulation in the preterm infant; however there is conflicting evidence on the interaction of these gasotransmitters, and their overall contribution to the microcirculation in newborns is not known. The aim of this study was to measure the levels of all 3 gasotransmitters, characterise their interrelationships and elucidate their combined effects on microvascular blood flow. Methods 90 preterm neonates were studied at 24h postnatal age. Microvascular studies were performed by laser Doppler. Arterial COHb levels (a measure of CO) were determined through co-oximetry. NO was measured as nitrate and nitrite in urine. H2S was measured as thiosulphate by liquid chromatography. Relationships between levels of the gasotransmitters and microvascular blood flow were assessed through partial correlation controlling for the influence of gestational age. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow and derive a theoretical model of their interactions. Results No relationship was observed between NO and CO (p = 0.18, r = 0.18). A positive relationship between NO and H2S (p = 0.008, r = 0.28) and an inverse relationship between CO and H2S (p = 0.01, r = -0.33) exists. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow. The model with the best fit is presented. Conclusions The relationships between NO and H2S, and CO and H2S may be of importance in the preterm newborn, particularly as NO levels in males are associated with higher H2S levels and higher microvascular blood flow and CO in females appears to convey protection against vascular dysregulation. Here we present a theoretical model of these interactions and their overall effects on microvascular flow in the preterm newborn, upon which future mechanistic studies may be based.The authors would like to acknowledge the parents of the neonates enrolled in the 2CANS study for their participation, the staff of the Kaleidoscope Neonatal Intensive Care Unit at the John Hunter Children’s Hospital, and Kimberly-Clark Australia for providing the diapers used in this stud

Sequence Stratigraphy and the Interpretation of Neoproterozoic Earth History

The application of sequence stratigraphy to Neoproterozoic successions is important for improving the resolution of time-correlation within individual sedimentary basins and potentially at a global scale. The methodology is illustrated in this paper by reference to two contrasting examples from the Flinders Ranges (Adelaide geosyncline) of South Australia, where the younger part of the Neoproterozoic to earliest Cambrian succession (∼ 770 Ma to ∼ 540 Ma) has been divided into thirteen unconformity-bounded depositional sequences. One of the most prominent sequence boundaries, at or near the base of the Wonoka Formation, is characterized by a series of buried canyons as much as 1 km deep. High-resolution sequence-stratigraphic studies at Umberatana syncline continue to support the view that the canyons were cut subaerially and filled by fluvial and shallow-water sediments. In contrast to the Wonoka canyons, sequence boundaries interpreted at the base of the Nuccaleena Formation/Seacliff Sandstone and near the top of the ABC Range Quartzite are relatively subtle, with only limited evidence for erosion and valley incision. Four sequence boundaries, at the level of the Sturtian and Marinoan (Varanger?) glacial deposits and in the vicinity of the Precambrian-Cambrian boundary, are thought to correlate with surfaces in the Amadeus basin of central Australia. Other prominent sequence boundaries, including the Wonoka canyons and surfaces within the upper part of the Wonoka Formation and at the base of the Ediacara Member of the Rawnsley Quartzite, correspond with a relatively condensed section in the Amadeus basin, and their lateral persistence beyond the Adelaide geosyncline is therefore difficult to evaluate. Given the lack of precision in biostratigraphy and isotope geochemistry in Neoproterozoic rocks, and in a marked departure from Phanerozoic practice, we recommend placement of a terminal Proterozoic GSSP at a sequence boundary. A prime candidate in Australia is the sequence boundary at the base of the Nuccaleena Formation/Seacliff Sandstone, immediately above the Marinoan glacial rocks in the Adelaide geosyncline, and its likely correlative at or near the base of the Gaylad Sandstone in the Amadeus basin

Divergent evolution of protein conformational dynamics in dihydrofolate reductase.

Molecular evolution is driven by mutations, which may affect the fitness of an organism and are then subject to natural selection or genetic drift. Analysis of primary protein sequences and tertiary structures has yielded valuable insights into the evolution of protein function, but little is known about the evolution of functional mechanisms, protein dynamics and conformational plasticity essential for activity. We characterized the atomic-level motions across divergent members of the dihydrofolate reductase (DHFR) family. Despite structural similarity, Escherichia coli and human DHFRs use different dynamic mechanisms to perform the same function, and human DHFR cannot complement DHFR-deficient E. coli cells. Identification of the primary-sequence determinants of flexibility in DHFRs from several species allowed us to propose a likely scenario for the evolution of functionally important DHFR dynamics following a pattern of divergent evolution that is tuned by cellular environment

In vivo validation of a miniaturized electrochemical oxygen sensor for measuring intestinal oxygen tension

Recent advances in the fields of electronics and microfabrication techniques have led to the development of implantable medical devices for use within the field of precision medicine. Monitoring visceral surface tissue O2 tension (ptO2) by means of an implantable sensor is potentially useful in many clinical situations including the peri-operative management of patients undergoing intestinal resection and anastomosis. This concept could provide a means by which treatment could be tailored to individual patients. This study describes the in vivo validation of a novel miniaturised electrochemical O2 sensor to provide real-time data on intestinal ptO2. A single O2 sensor was placed onto the serosal surface of the small intestine of anaesthetised rats that were exposed to ischaemic (superior mesenteric artery occlusion) and hypoxaemic (alterations in inspired fractional O2 concentrations) insults. Control experiments demonstrated that the sensors function and remain stable in an in vivo environment. Intestinal ptO2 decreased following superior mesenteric artery occlusion and with reductions in inspired O2 concentrations. These results were reversible after reinstating blood flow or increasing inspired O2 concentrations. We have successfully developed an anaesthetised rat intestinal ischaemic and hypoxic model for validation of a miniaturised O2 sensor to provide real-time measurement of intestinal ptO2. Our results support further validation of the sensors in physiological conditions using a large animal model to provide evidence of their use in clinical applications where monitoring visceral surface tissue O2 tension is important

Why volunteer? What stimulates involvement in a stem peer learning facilitation program?

There is an acknowledged need for strategies to enhance participation, learning and graduate capabilities for students engaged in STEM disciplines given the central importance of these skills to the future economy. The STIMulate program provides support for learning across maths, science and IT to all QUT coursework students regardless of course of study or campus. Central to the success of the program is the provision of face-to-face peer support by a team of high-achieving, experienced student volunteers; the Peer Learning Facilitators (PLFs). Understanding the motivations and expectations of the diverse team of STIMulate student volunteers is necessary to appropriately manage the program. A survey instrument was adapted from the Volunteer Functions Inventory (Clary, Snyder, Ridge, Copeland, Stukas, Haugen & Meine, 1998) to assess three drivers of participation - autonomy, mastery and purpose, and provided to all commencing PLFs at the initial 2016 training session. Principal Component Analysis (PCA) identified three classifications of motivators for beginning PLFs: relationships and experiences (most important criteria), intrinsic motivators and extrinsic motivators (least important criteria). The findings of this work represent an important first step towards enhancing evidence-based practice for the management, reward and recognition of student volunteers engaged in academic support programs

From the Square Lattice to the Checkerboard Lattice : Spin Wave and Large-n Analysis

Within a spin wave analysis and a fermionic large-n limit, it is shown that the antiferromagnetic Heisenberg model on the checkerboard lattice may have different ground states, depending on the spin size $S$. Through an additional exchange interaction that corresponds to an inter-tetrahedra coupling, the stability of the N\'eel state has been explored for all cases from the square lattice to the isotropic checkerboard lattice. Away from the isotropic limit and within the linear spin wave approximation, it is shown that there exists a critical coupling for which the local magnetization of the N\'eel state vanishes for any value of the spin $S$. One the other hand, using the Dyson-Maleev approximation, this result is valid only in the case $S= \frac12$ and the limit between a stable and an unstable N\'eel state is at S=1. For $S= \frac12$, the fermionic large-n limit suggests that the ground state is a valence bond solid build with disconnected 4-spins singlets. This analysis indicates that for low spin and in the isotropic limit, the checkerboard antiferromagnet may be close to an instability between an ordered S=0 ground state and a magnetized ground state.Comment: 9 pages (revtex two column), 11 figures. Higher quality figures are available at http://benjamin.canals.free.fr/ukpublications.html Version to be published in Phys. Rev.

Inherent Structural Disorder and Dimerisation of Murine Norovirus NS1-2 Protein

Human noroviruses are highly infectious viruses that cause the majority of acute, non-bacterial epidemic gastroenteritis cases worldwide. The first open reading frame of the norovirus RNA genome encodes for a polyprotein that is cleaved by the viral protease into six non-structural proteins. The first non-structural protein, NS1-2, lacks any significant sequence similarity to other viral or cellular proteins and limited information is available about the function and biophysical characteristics of this protein. Bioinformatic analyses identified an inherently disordered region (residues 1–142) in the highly divergent N-terminal region of the norovirus NS1-2 protein. Expression and purification of the NS1-2 protein of Murine norovirus confirmed these predictions by identifying several features typical of an inherently disordered protein. These were a biased amino acid composition with enrichment in the disorder promoting residues serine and proline, a lack of predicted secondary structure, a hydrophilic nature, an aberrant electrophoretic migration, an increased Stokes radius similar to that predicted for a protein from the pre-molten globule family, a high sensitivity to thermolysin proteolysis and a circular dichroism spectrum typical of an inherently disordered protein. The purification of the NS1-2 protein also identified the presence of an NS1-2 dimer in Escherichia coli and transfected HEK293T cells. Inherent disorder provides significant advantages including structural flexibility and the ability to bind to numerous targets allowing a single protein to have multiple functions. These advantages combined with the potential functional advantages of multimerisation suggest a multi-functional role for the NS1-2 protein

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery