ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars

The atypical protein kinase ALPK1 is activated by the bacterial nucleotide sugar ADP-heptose and phosphorylates TIFA to switch on a signaling pathway that combats microbial infection. In contrast, ALPK1 mutations cause two human diseases: the ALPK1[T237M] and ALPK1[Y254C] mutations underlie ROSAH syndrome (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis, and migraine headache), while the ALPK1[V1092A] mutation accounts for 45% of spiradenoma and 30% of spiradenocarcinoma cases studied. In this study, we demonstrate that unlike wild-type (WT) ALPK1, the disease-causing ALPK1 mutants trigger the TIFA-dependent activation of an NF-κB/activator protein 1 reporter gene in the absence of ADP-heptose, which can be suppressed by either of two additional mutations in the ADP-heptose binding site that prevent the activation of WT ALPK1 by ADP-heptose. These observations are explained by our key finding that although ALPK1[T237M] and ALPK1[V1092A] are activated by bacterial ADP-heptose, they can also be activated by nucleotide sugars present in human cells (UDP-mannose, ADP-ribose, and cyclic ADP-ribose) which can be prevented by disruption of the ADP-heptose binding site. The ALPK1[V1092A] mutant was also activated by GDP-mannose, which did not activate ALPK1[T237M]. These are new examples of disease-causing mutations permitting the allosteric activation of an enzyme by endogenous molecules that the WT enzyme does not respond to. We propose that the loss of the specificity of ALPK1 for bacterial ADP-heptose underlies ROSAH syndrome and spiradenoma/spiradenocarcinoma caused by ALPK1 mutation.</p

ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars

The atypical protein kinase ALPK1 is activated by the bacterial nucleotide sugar ADP-heptose and phosphorylates TIFA to switch on a signaling pathway that combats microbial infection. In contrast, ALPK1 mutations cause two human diseases: the ALPK1[T237M] and ALPK1[Y254C] mutations underlie ROSAH syndrome (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis, and migraine headache), while the ALPK1[V1092A] mutation accounts for 45% of spiradenoma and 30% of spiradenocarcinoma cases studied. In this study, we demonstrate that unlike wild-type (WT) ALPK1, the disease-causing ALPK1 mutants trigger the TIFA-dependent activation of an NF-κB/activator protein 1 reporter gene in the absence of ADP-heptose, which can be suppressed by either of two additional mutations in the ADP-heptose binding site that prevent the activation of WT ALPK1 by ADP-heptose. These observations are explained by our key finding that although ALPK1[T237M] and ALPK1[V1092A] are activated by bacterial ADP-heptose, they can also be activated by nucleotide sugars present in human cells (UDP-mannose, ADP-ribose, and cyclic ADP-ribose) which can be prevented by disruption of the ADP-heptose binding site. The ALPK1[V1092A] mutant was also activated by GDP-mannose, which did not activate ALPK1[T237M]. These are new examples of disease-causing mutations permitting the allosteric activation of an enzyme by endogenous molecules that the WT enzyme does not respond to. We propose that the loss of the specificity of ALPK1 for bacterial ADP-heptose underlies ROSAH syndrome and spiradenoma/spiradenocarcinoma caused by ALPK1 mutation.</p

Combining to innovate: A collaborative interprofessional learning approach to delivering Tobacco Use Prevention and Cessation (TUPAC) education for undergraduate oral health students

This paper provides a description of a pilot project in Tobacco Use Prevention and Cessation (TUPAC) in response to a national and international trend to include TUPAC curriculum components in the clinical education of undergraduate oral health students. In order to deliver quality brief intervention strategies for smokers a need to adequately prepare oral health students was identified during student clinical placements. An interprofessional (IP) project team was established with membership from the University of Adelaide’s School of Dentistry, QuitSA, Cancer Council SA, the South Australian Dental Service (SADS) Somerton Park and TAFESA’s Faculty of Dental Studies to streamline the efficient use of resources and most importantly draw on a diverse range of interprofessional health care expertise. On the website for The UK Centre for the Advancement of Interprofessional Education (CAIPE) (2002) it states that “Interprofessional education occurs when two or more professions learn from and about each other to improve collaboration and the quality of care”. Through interprofessional learning (IPL) in classroom and clinical settings, second year Bachelor and Advanced Diploma oral health students were provided with the opportunity to develop an understanding of the respective roles of each health professional responsible for delivering positive health initiatives in the area of TUPAC. With limited national oral health curricula in the area of TUPAC, the project team forged links with the University of Manitoba’s Dental Hygiene Program, and the convenor of the TUPAC in Dental and Dental Hygiene Undergraduate Education European Workshops for curriculum benchmarking against evidence based criteria. Most importantly as the IP concept of health care considers the patient at the centre of the health care team, assessment was designed to encourage a patient centred approach through the review and analysis of a clinical case study. A formal evaluation of this project is currently in progress, however results were not yet available at the time of publication

Baseline incidence of adverse birth outcomes and infant influenza and pertussis hospitalisations prior to the introduction of influenza and pertussis vaccination in pregnancy: a data linkage study of 78 382 mother-infant pairs, Northern Territory, Australia, 1994-2015

We conducted probabilistic data linkage of three population datasets for the Northern Territory (NT), Australia, to describe the incidence of preterm births, stillbirths, low birthweight and small for gestational age (SGA) per 1000 NT births; and influenza and pertussis hospitalisations per 1 00 000 NT births in infants <7 months of age, in a pre-maternal vaccination era. The Perinatal Trends dataset (1994–2014) formed the cohort of 78 382 births. Aboriginal mother–infant pairs (37%) had disproportionately higher average annual rates (AR) for all adverse birth outcomes compared to their non-Aboriginal counterparts; rate ratios: preterm births 2.2 (AR 142.4 vs. 64.7); stillbirths 2.3 (AR 10.8 vs. 4.6); low birthweight 2.9 (AR 54 vs. 19); and SGA 1.7 (AR 187 vs. 111). Hospitalisation (2000–2015) and Immunisation Register datasets (1994–2015), showed that influenza hospitalisations (n = 53) and rates were 42.3 times higher in Aboriginal infants (AR 254 vs. 6); and that pertussis hospitalisations (n = 37) were 7.1 times higher in Aboriginal infants (AR 142.5 vs. 20.2) compared to non-Aboriginal infants. These baseline data are essential to assess the safety and effectiveness of influenza and pertussis vaccinations in pregnant women from the NT. Remote living Aboriginal women and infants stand to benefit the most from these vaccines.This study was funded by a National Health and Medical Research Council (NHMRC) Project Grant (APP1091491). LMc was supported by an Australian Postgraduate Award scholarship provided by Charles Darwin University of the Northern Territory and an Enhanced Living scholarship provided by Menzies as part of the Doctor of Philosophy (PhD) program. TS holds a Career Development Fellowship from the NHMRC (GNT 1111657). MJB was supported by an NHMRC Early Career Fellowship (GNT1088733)

The shortage of kidneys for transplantation in Australia

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.Timothy Mathew, Randall Faull and Paul Snellin

Propionate has protective and anti-inflammatory effects on the blood–brain barrier

Production of short-chain fatty acids (SCFAs) from dietary substrates by the gut microbiota is associated with health, with these metabolites influencing the host via the ‘gut–brain axis’. Micromolar quantities of microbially derived SCFAs are taken up from the gut and reach systemic circulation, where they can influence host gene expression through a variety of largely unknown mechanisms. The blood–brain barrier (BBB) is the major interface between the circulation and central nervous system, and is critically involved in the pathogenesis of neuroinflammatory disorders such as stroke and vascular dementia. We hypothesized exposure of the BBB to SCFAs influences barrier integrity and function. To test our hypothesis, we investigated the in vitro effects of a physiologically relevant concentration (1 μM) of propionate upon the human immortalised cerebromicrovascular endothelial cell line hCMEC/D3. Propionate is produced by the microbiota from dietary glucans, and is biologically active via the G protein coupled receptors FFAR2 and FFAR3. It is a highly potent FFAR2 agonist (agonist activity 3.99) and has close to optimal ligand efficiency (-ΔG=1.19 kcal mol-1 atom-1) for this receptor. Notably, FFAR3 is expressed on the vascular endothelium and a likely target for propionate in the BBB. After confirming the presence of FFAR3 on hCMEC/D3 cells, we undertook an unbiased transcriptomic analysis of confluent hCMEC/D3 monolayers treated or not for 24 h with 1 μM propionate, supported by in vitro validation of key findings and assessment of functional endothelial permeability barrier properties. Propionate treatment had a significant (PFDR < 0.1) effect on the expression of 1136 genes: 553 upregulated, 583 downregulated. Propionate inhibited several inflammation-associated pathways: namely, TLR-specific signalling, NFkappaB signalling, and cytosolic DNA-sensing. Functional validation of these findings confirmed the down-regulation of TLR signalling by propionate, achieved primarily through down-regulation of endothelial CD14 expression. Accordingly, propionate prevented LPS-induced increases in paracellular permeability to 70 kDa FITC-dextran and loss of transendothelial electrical resistance. Enrichr analysis indicated the activation by propionate of the NFE2L2 (NRF2)-driven protective response against oxidative stress. Confirming these data, propionate limited free reactive oxygen species induction by the mitochondrial respiratory inhibitor rotenone. Together, these data strongly suggest the SCFA propionate contributes to maintaining BBB integrity and protecting against inflammatory challenge by downregulating BBB responsiveness. In addition to its well-described effects on cholesterol metabolism, maintenance of propionate levels in the circulation may be an additional mechanism whereby a glucan-containing diet protects against neurovascular disease

Effect of Field-Line Curvature on the Ionospheric Accessibility of Relativistic Electron Beam Experiments

Magnetosphere-ionosphere coupling is a particularly important process that regulates and controls magnetospheric dynamics such as storms and substorms. However, in order to understand magnetosphere-ionosphere coupling it is necessary to understand how regions of the magnetosphere are connected to the ionosphere. It has been proposed that this connection may be established by firing electron beams from satellites that can reach an ionospheric footpoint creating detectable emissions. This type of experiment would greatly aid in identifying the relationship between convection processes in the magnetotail and the ionosphere and how the plasma sheet current layer evolves during the growth phase preceding substorms. For practical purposes, the use of relativistic electron beams with kinetic energy on the order of 1 MeV would be ideal for detectability. However, Porazik et al. (2014) has shown that, for relativistic particles, higher order terms of the magnetic moment are necessary for consideration of the ionospheric accessibility of the beams. These higher order terms are related to gradients and curvature in the magnetic field and are typically unimportant unless the beam is injected along the magnetic field direction, such that the zero order magnetic moment is small. In this article, we address two important consequences related to these higher order terms. First, we investigate the consequences for satellites positioned in regions subject to magnetotail stretching and demonstrate systematically how curvature affects accessibility. We find that curvature can reduce accessibility for beams injected from the current sheet, but can increase accessibility for beams injected just above the current sheet. Second, we investigate how detectability of ionospheric precipitation of variable energy field-aligned electron beams could be used as a constraint on field-line curvature, which would be valuable for field-line reconstruction and/or stability analysis

A platform in the use of medicines to treat chronic hepatitis C (PLATINUM C) protocol for a prospective treatment registry of real world o

Background Safe, highly curative, short course, direct acting antiviral (DAA) therapies are now available to treat chronic hepatitis C. DAA therapy is freely available to all adults chronically infected with the hepatitis C virus (HCV) in Australia. If left untreated, hepatitis C may lead to progressive hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Australia is committed to eliminating hepatitis as a public health threat by 2030 set by the World Health Organization. However, since the introduction of funded DAA treatment, uptake has been suboptimal. Australia needs improved strategies for testing, treatment uptake and treatment completion to address the persisting hepatitis C public health problem. PLATINUM C is a HCV treatment registry and research platform for assessing the comparative effectiveness of alternative interventions for achieving virological cure. Methods PLATINUM C will prospectively enrol people with active HCV infection confirmed by recent detection of HCV ribonucleic acid (RNA) in blood. Those enrolled will agree to allow standardised collection of demographic, lifestyle, treatment, virological outcome and other relevant clinical data to better inform the future management of HCV infection. The primary outcome is virological cure evidenced by sustained virological response (SVR), which is defined as a negative HCV PCR result 6 to 18 months after initial prescription of DAA therapy and no less than 12 weeks after the completion of treatment. Study participants will be invited to opt-in to medication adherence monitoring and quality of life assessments using validated self-reported instruments (EQ-5D-5L). Discussion PLATINUM C is a treatment registry and platform for nesting pragmatic trials. Data collected will inform the design, development and implementation of pragmatic trials. The digital infrastructure, study procedures and governing systems established by the registry will allow PLATINUM C to support a wider research platform in the management of hepatitis C in primary care. Trial registration The trial is registered with the Australia and New Zealand Clinical Trials Register (ACTRN12619000023156). Date of registration: 10/01/2019

Method for Approximating Field-Line Curves Using Ionospheric Observations of Energy-Variable Electron Beams Launched From Satellites

Using electron beam accelerators attached to satellites in Earth orbit, it may be possible to measure arc length and curvature of field-lines in the inner magnetosphere if the accelerator is designed with the capability to vary the beam energy. In combination with additional information, these measurements would be very useful in modeling the magnetic field of the inner magnetosphere. For this purpose, a three step data assimilation modeling approach is discussed. The first step in the procedure would be to use prior information to obtain an initial forecast of the inner magnetosphere. Then, a family of curves would be defined that satisfies the observed geometric attributes measured by the experiments, and the prior forecast would then be used to optimize the curve with respect to the allowed degrees of freedom. Finally, this approximation of the field-line would be used to improve the initial forecast of the inner magnetosphere, resulting in a description of the system that is optimally consistent with both the prior information and the measured curvature and arc length. This article details the method by which a family of possible approximations of the field-line may be defined via a numerical procedure, which is central to the three step approach. This method serves effectively as a pre-conditioner for parameter estimation problems using field-line curvature and arc length measurements in combination with other measurements

The effects of temperature and body mass on jump performance of the locust Locusta migratoria

Locusts jump by rapidly releasing energy from cuticular springs built into the hind femur that deform when the femur muscle contracts. This study is the first to examine the effect of temperature on jump energy at each life stage of any orthopteran. Ballistics and high-speed cinematography were used to quantify the energy, distance, and take-off angle of the jump at 15, 25, and 35°C in the locust Locusta migratoria. Allometric analysis across the five juvenile stages at 35°C reveals that jump distance (D; m) scales with body mass (M; g) according to the power equation D = 0.35M0.17±0.08 (95% CI), jump take-off angle (A; degrees) scales as A = 52.5M0.00±0.06, and jump energy (E; mJ per jump) scales as E = 1.91M1.14±0.09. Temperature has no significant effect on the exponent of these relationships, and only a modest effect on the elevation, with an overall Q10 of 1.08 for jump distance and 1.09 for jump energy. On average, adults jump 87% farther and with 74% more energy than predicted based on juvenile scaling data. The positive allometric scaling of jump distance and jump energy across the juvenile life stages is likely facilitated by the concomitant relative increase in the total length (Lf+t; mm) of the femur and tibia of the hind leg, Lf+t = 34.9M0.37±0.02. The weak temperature-dependence of jump performance can be traced to the maximum tension of the hind femur muscle and the energy storage capacity of the femur's cuticular springs. The disproportionately greater jump energy and jump distance of adults is associated with relatively longer (12%) legs and a relatively larger (11%) femur muscle cross-sectional area, which could allow more strain loading into the femur's cuticular springs. Augmented jump performance in volant adult locusts achieves the take-off velocity required to initiate flight.Edward P. Snelling, Christie L. Becker, Roger S. Seymou