Thiol metabolism in the parasitic nematode Haemonchus contortus

University of Technology, Sydney. Faculty of Science.Haemonchus contortus is an important parasitic nematode, both economically and pathologically. The emergence of widespread drug resistance requires new drug or vaccine targets to be identified. The requirement of aerobic organisms to control damage caused by reactive oxygen species and, the increased necessity of parasites to overcome the host immune response, has led to the investigation of antioxidant systems as potential targets. This work examines the thioredoxin antioxidant system in H. contortus, specifically the thioredoxin reductase and peroxiredoxin enzymes, to characterise their activity and determine if they are potential targets for parasite control. H. contortus contains two TrxRs, a cytoplasmic enzyme HcTrxRl with a selenocysteine in the active site, similar to the mammalian TrxR, and a mitochondrial enzyme HcTrxR2 with a nematode unique active site. HcTrxRl showed broad activity with thioredoxins from E. coli, sheep, and H. contortus while HcTrxR2 had high activity with only the mitochondrial H. contortus thioredoxin 1. Importantly, HcTrxRl was found to be more sensitive to the black tea inhibitor theaflavin than the selenocysteine containing mammalian TrxR, demonstrating the differences in the enzymes susceptibilities to inhibitors. To determine the function of the TrxR enzymes in nematodes, knockout (KO) strains of Caenorhabditis elegans were examined. TrxRl -/-KO worms were more sensitive to free radical attack and also to the anthelmintic ivermectin; while TrxR2 -/- KO eggs were highly sensitive to sodium hypochlorite. This demonstrates that inhibition of these enzymes would sensitise the nematodes to the host's immune attack. H. contortus contains two peroxiredoxins, the mitochondrial HcPrxl and the cytoplasmic HcPrx2. The activity of both peroxiredoxins was specific for the thioredoxin system; however, both peroxiredoxins were also able to be regenerated by the glutathione system when coupled to the nematode specific H. contortus thioredoxin 5. Both enzymes were stable to high concentrations of hydrogen peroxide which demonstrates different functions to their mammalian counterparts. A specific inhibitor of these peroxiredoxins was also identified which has minimal mammalian cytotoxicity. HcPrxl was found to be involved in drug resistance while HcPrx2 was found to be secreted and highly immunogenic. Analysis of homologous genes in C. elegans showed that both peroxiredoxin KO worms were sensitive to free radical attack; however, only the cytoplasmic CePrx2 KO C. elegans were sensitive to external oxidants. Overall, this work adds to the knowledge of H. contortus biology and identifies the enzymes of the thioredoxin system as potential drug or vaccine targets for parasite control

Three classes of ligands each bind to distinct sites on the orphan G protein-coupled receptor GPR84

Medium chain fatty acids can activate the pro-inflammatory receptor GPR84 but so also can molecules related to 3,3′-diindolylmethane. 3,3′-Diindolylmethane and decanoic acid acted as strong positive allosteric modulators of the function of each other and analysis showed the affinity of 3,3′-diindolylmethane to be at least 100 fold higher. Methyl decanoate was not an agonist at GPR84. This implies a key role in binding for the carboxylic acid of the fatty acid. Via homology modelling we predicted and confirmed an integral role of arginine172, located in the 2nd extracellular loop, in the action of decanoic acid but not of 3,3′-diindolylmethane. Exemplars from a patented series of GPR84 antagonists were able to block agonist actions of both decanoic acid and 3,3′-diindolylmethane at GPR84. However, although a radiolabelled form of a related antagonist, [3H]G9543, was able to bind with high affinity to GPR84, this was not competed for by increasing concentrations of either decanoic acid or 3,3′-diindolylmethane and was not affected adversely by mutation of arginine172. These studies identify three separable ligand binding sites within GPR84 and suggest that if medium chain fatty acids are true endogenous regulators then co-binding with a positive allosteric modulator would greatly enhance their function in physiological settings

Optimal electrode position for abdominal functional electrical stimulation

Abdominal functional electrical stimulation (abdominal FES) improves respiratory function. Despite this, clinical use remains low, possibly due to lack of agreement on the optimal electrode position. This study aimed to ascertain the optimal electrode position for abdominal FES, assessed by expiratory twitch pressure. Ten able-bodied participants received abdominal FES using electrodes placed: 1) on the posterolateral abdominal wall and at the motor points of 2) the external oblique muscles plus rectus abdominis muscles, and 3) the external obliques alone. Gastric (Pga) and esophageal (Pes) twitch pressures were measured using a gastroesophageal catheter. Single-stimulation pulses were applied at functional residual capacity during step increments in stimulation current to maximal tolerance or until Pga plateaued. Stimulation applied on the posterolateral abdominal wall led to a 71% and 53% increase in Pga and Pes, respectively.compared with stimulation of the external oblique and rectus abdominis muscles (P < 0.001) and a 95% and 56% increase in Pga and Pes, respectively.compared with stimulation of the external oblique muscles alone (P < 0.001). Stimulation of both the external oblique and rectus abdominis muscles led to an 18.3% decrease in Pg.compared with stimulation of only the external oblique muscles (P = 0.040), with inclusion of the rectus abdominis having no effect on Pes (P = 0.809). Abdominal FES applied on the posterolateral abdominal wall generated the highest expiratory twitch pressures. As expiratory pressure is a good indicator of expiratory muscle strength and, thus, cough efficacy, we recommend this electrode position for all therapeutic applications of abdominal FES. NEW & NOTEWORTHY While abdominal functional electrical stimulation (abdominal FES) can improve respiratory function, clinical use remains low. This is at least partly due to lack of agreement on the optimal electrode position. Therefore, this study aimed to ascertain the optimal electrode position for abdominal FES. We show that electrodes placed on the posterolateral abdominal wall generated the highest expiratory twitch pressures. As such, we recommend this electrode position for all therapeutic applications of abdominal FES

Length is a Curse and a Blessing for Document-level Semantics

In recent years, contrastive learning (CL) has been extensively utilized to recover sentence and document-level encoding capability from pre-trained language models. In this work, we question the length generalizability of CL-based models, i.e., their vulnerability towards length-induced semantic shift. We verify not only that length vulnerability is a significant yet overlooked research gap, but we can devise unsupervised CL methods solely depending on the semantic signal provided by document length. We first derive the theoretical foundations underlying length attacks, showing that elongating a document would intensify the high intra-document similarity that is already brought by CL. Moreover, we found that isotropy promised by CL is highly dependent on the length range of text exposed in training. Inspired by these findings, we introduce a simple yet universal document representation learning framework, LA(SER)$^{3}$: length-agnostic self-reference for semantically robust sentence representation learning, achieving state-of-the-art unsupervised performance on the standard information retrieval benchmark.Comment: Accepted at EMNLP 2023. Our code is publicly available at https://github.com/gowitheflow-1998/LA-SER-cube

Chlamydia pneumoniae: An Etiologic Agent for Late-Onset Dementia

The disease known as late-onset Alzheimer\u27s disease is a neurodegenerative condition recognized as the single most common form of senile dementia. The condition is sporadic and has been attributed to neuronal damage and loss, both of which have been linked to the accumulation of protein deposits in the brain. Significant progress has been made over the past two decades regarding our overall understanding of the apparently pathogenic entities that arise in the affected brain, both for early-onset disease, which constitutes approximately 5% of all cases, as well as late-onset disease, which constitutes the remainder of cases. Observable neuropathology includes: neurofibrillary tangles, neuropil threads, neuritic senile plaques and often deposits of amyloid around the cerebrovasculature. Although many studies have provided a relatively detailed knowledge of these putatively pathogenic entities, understanding of the events that initiate and support the biological processes generating them and the subsequent observable neuropathology and neurodegeneration remain limited. This is especially true in the case of late-onset disease. Although early-onset Alzheimer\u27s disease has been shown conclusively to have genetic roots, the detailed etiologic initiation of late-onset disease without such genetic origins has remained elusive. Over the last 15 years, current and ongoing work has implicated infection in the etiology and pathogenesis of late-onset dementia. Infectious agents reported to be associated with disease initiation are various, including several viruses and pathogenic bacterial species. We have reported extensively regarding an association between late-onset disease and infection with the intracellular bacterial pathoge

Inspiratory muscle responses to sudden airway occlusion in chronic obstructive pulmonary disease

Brief airway occlusion produces a potent reflex inhibition of inspiratory muscles that is thought to protect against aspiration. Its duration is prolonged in asthma and obstructive sleep apnea. We assessed this inhibitory reflex (IR) in chronic obstructive pulmonary disease (COPD). Reflex responses to brief (250 ms) inspiratory occlusions were measured in 18 participants with moderate to severe COPD (age 73 ± 11 yr) and 17 healthy age-matched controls (age 72 ± 6 yr). We compared the incidence and properties of the IR between groups. Median eupneic preocclusion electromyographic activity was higher in the COPD group than controls (9.4 μV vs. 5.2 μV, P = 0.001). Incidence of the short-latency IR was higher in the COPD group compared with controls (15 participants vs. 7 participants, P = 0.010). IR duration for scalenes was similar for the COPD and control groups [73 ± 37 ms (means ± SD) and 90 ± 50 ms, respectively] as was the magnitude of inhibition. IRs in the diaphragm were not detected in the controls but were present in 9 participants of the COPD group (P = 0.001). The higher incidence of the IR in the COPD group than in the age-matched controls may reflect the increased inspiratory neural drive in the COPD group. This higher drive counteracts changes in chest wall and lung mechanics. However, when present, the reflex was similar in size and duration in the two groups. The relation between the IR in COPD and swallowing function could be assessed. NEW & NOTEWORTHY A potent short-latency reflex inhibition of inspiratory muscles produced by airway occlusion was tested in people with COPD and age-matched controls. The reflex was more prevalent in COPD, presumably due to an increased neural drive to breathe. When present, the reflex was similar in duration in the two groups, longer than historical data for younger control groups. The work reveals novel differences in reflex control of inspiratory muscles due to aging as well as COPD

Abdominal functional electrical stimulation to augment respiratory function in spinal cord injury

Background: Functional electrical stimulation (FES) is the application of electrical pulses to a nerve to achieve a functional muscle contraction. Surface electrical stimulation of the nerves that innervate the abdominal muscles, termed abdominal FES, can cause the abdominal muscles to contract, even when paralysed after spinal cord injury. As the abdominal muscles are the major expiratory muscles, and commonly partially or completely paralysed in tetraplegia, abdominal FES offers a promising method of improving respiratory function for this patient group. Objective: The aim of the article is to provide readers with a better understanding of how abdominal FES can be used to improve the health of the spinal cord–injured population. Methods: A narrative review of the abdominal FES literature was performed. Results: Abdominal FES can achieve an immediate effective cough in patients with tetraplegia, while the repeated application over 6 weeks of abdominal FES can improve unassisted respiratory function. Ventilator duration and tracheostomy cannulation time can also be reduced with repeated abdominal FES. Conclusion: Abdominal FES is a noninvasive method to achieve functional improvements in cough and respiratory function in acute and chronically injured people with tetraplegia. Potential practical outcomes of this include reduced ventilation duration, assisted tracheostomy decannulation, and a reduction in respiratory complications. All of these outcomes can contribute to reduced morbidity and mortality, improved quality of life, and significant potential cost savings for local health care providers

Breath-by-Breath Analysis of Cardiorespiratory Interaction for Quantifying Developmental Maturity in Premature Infants

Breath-by-breath analysis of cardiorespiratory interaction for quantifying developmental maturity in premature infants. J Appl Physiol 112: 859-867, 2012. First published December 15, 2011; doi:10.1152/japplphysiol.01152.2011.-In healthy neonates, connections between the heart and lungs through brain stem chemosensory pathways and the autonomic nervous system result in cardiorespiratory synchronization. This interdependence between cardiac and respiratory dynamics can be difficult to measure because of intermittent signal quality in intensive care settings and variability of heart and breathing rates. We employed a phase-based measure suggested by Sch fer and coworkers (Sch fer C, Rosenblum MG, Kurths J, Abel HH. Nature 392: 239-240, 1998) to obtain a breath-by-breath analysis of cardiorespiratory interaction. This measure of cardiorespiratory interaction does not distinguish between cardiac control of respiration associated with cardioventilatory coupling and respiratory influences on the heart rate associated with respiratory sinus arrhythmia. We calculated, in sliding 4-min windows, the probability density of heartbeats as a function of the concurrent phase of the respiratory cycle. Probability density functions whose Shannon entropy had a \u3c 0.1% chance of occurring from random numbers were classified as exhibiting interaction. In this way, we analyzed 18 infant-years of data from 1,202 patients in the Neonatal Intensive Care Unit at University of Virginia. We found evidence of interaction in 3.3 patient-years of data (18%). Cardiorespiratory interaction increased several-fold with postnatal development, but, surprisingly, the rate of increase was not affected by gestational age at birth. We find evidence for moderate correspondence between this measure of cardiorespiratory interaction and cardioventilatory coupling and no evidence for respiratory sinus arrhythmia, leading to the need for further investigation of the underlying mechanism. Such continuous measures of physiological interaction may serve to gauge developmental maturity in neonatal intensive care patients and prove useful in decisions about incipient illness and about hospital discharge

Continuous heating of a giant X-ray flare on Algol

Giant flares can release large amounts of energy within a few days: X-ray emission alone can be up to ten percent of the star's bolometric luminosity. These flares exceed the luminosities of the largest solar flares by many orders of magnitude, which suggests that the underlying physical mechanisms supplying the energy are different from those on the Sun. Magnetic coupling between the components in a binary system or between a young star and an accretion disk has been proposed as a prerequisite for giant flares. Here we report X-ray observations of a giant flare on Algol B, a giant star in an eclipsing binary system. We observed a total X-ray eclipse of the flare, which demonstrates that the plasma was confined to Algol B, and reached a maximum height of 0.6 stellar radii above its surface. The flare occurred around the south pole of Algol B, and energy must have been released continously throughout its life. We conclude that a specific extrastellar environment is not required for the presence of a flare, and that the processes at work are therefore similar to those on the Sun.Comment: Nature, Sept. 2 199