Objective
The study aim was to compare interictal encephalographic (EEG) functional network topology between people with well‐controlled idiopathic generalized epilepsy (WC‐IGE) and drug‐resistant ...IGE (DR‐IGE).
Methods
Nineteen participants with WC‐IGE, 18 with DR‐IGE, and 20 controls underwent a resting state, 64‐channel EEG. An artifact‐free epoch was bandpass filtered into the frequency range of high and low extended alpha. Weighted functional connectivity matrices were calculated. Mean degree, degree distribution variance, characteristic path length (L), clustering coefficient, small world index (SWI), and betweenness centrality were measured. A Kruskal–Wallis H‐test assessed effects across groups. Where significant differences were found, Bonferroni‐corrected Mann–Whitney pairwise comparisons were calculated.
Results
In the low alpha band (6–9 Hz), there was a significant difference in L at the three‐group level (p < .0001). This was lower in controls than both WC‐IGE and DR‐IGE (p < .0001 for both), with no difference in L between WC‐IGE and DR‐IGE. Mean degree (p = .031), degree distribution variance (p = .032), and SWI (p = .023) differed across the three groups in the high alpha band (10–12 Hz). Mean degree and degree distribution variance were lower in WC‐IGE than controls (p = .029 for both), and SWI was higher in WC‐IGE compared with controls (p = .038), with no differences in other pairwise comparisons.
Significance
IGE network topology is more regular in the low alpha frequency band, potentially reflecting a more vulnerable structure. WC‐IGE network topology is different from controls in the high alpha band. This may reflect drug‐induced network changes that have stabilized the WC‐IGE network by rendering it less likely to synchronize. These results are of potential importance in advancing the understanding of mechanisms of epilepsy drug resistance and as a possible basis for a biomarker of DR‐IGE.
With the development of ultra-high-throughput technologies, the cost of sequencing bacterial genomes has been vastly reduced. As more genomes are sequenced, less time can be spent manually annotating ...those genomes, resulting in an increased reliance on automatic annotation pipelines. However, automatic pipelines can produce inaccurate genome annotation and their results often require manual curation. Here, we discuss the automatic and manual annotation of bacterial genomes, identify common problems introduced by the current genome annotation process and suggests potential solutions.
The emergence of new pathogens is a major threat to public and veterinary health. Changes in bacterial habitat such as a switch in host or disease tropism are typically accompanied by genetic ...diversification. Staphylococcus aureus is a multi-host bacterial species associated with human and livestock infections. A microaerophilic subspecies, Staphylococcus aureus subsp. anaerobius, is responsible for Morel's disease, a lymphadenitis restricted to sheep and goats. However, the evolutionary history of S. aureus subsp. anaerobius and its relatedness to S. aureus are unknown. Population genomic analyses of clinical S. aureus subsp. anaerobius isolates revealed a highly conserved clone that descended from a S. aureus progenitor about 1000 years ago before differentiating into distinct lineages that contain African and European isolates. S. aureus subsp. anaerobius has undergone limited clonal expansion, with a restricted population size, and an evolutionary rate 10-fold slower than S. aureus. The transition to its current restricted ecological niche involved acquisition of a pathogenicity island encoding a ruminant host-specific effector of abscess formation, large chromosomal re-arrangements, and the accumulation of at least 205 pseudogenes, resulting in a highly fastidious metabolism. Importantly, expansion of ~87 insertion sequences (IS) located largely in intergenic regions provided distinct mechanisms for the control of expression of flanking genes, including a novel mechanism associated with IS-mediated anti-anti-sense decoupling of ancestral gene repression. Our findings reveal the remarkable evolutionary trajectory of a host-restricted bacterial pathogen that resulted from extensive remodelling of the S. aureus genome through an array of diverse mechanisms in parallel.
Nodulisporic acids (NAs) are structurally complex potent antiinsectan indole diterpenes. We previously reported the biosynthetic gene cluster for these metabolites in Hypoxylon pulicicidum and ...functionally characterised the first five steps of the biosynthetic pathway. Here we reveal a highly complex biosynthetic array, furnishing multiple end products through expression of cluster components in Penicillium paxilli. We show that seven additional cluster‐encoded gene products comprise the biosynthetic machinery that elaborate precursor NAF in this highly branched pathway. The combined action of these enzymes delivers 37 NA congeners including four major end products, NAA, NAA1, NAA2 and NAA4. The plethora of intermediates arises due to modification of the carboxylated prenyl tail by a single promiscuous P450 monooxygenase, NodJ, a pivotal branchpoint enzyme which produces four distinct biosynthetic products giving rise to the complex metabolic grid that characterises NA biosynthesis.
Nodulisporic acids are structurally complex potent antiinsectan natural products produced by the filamentous fungus Hypoxylon pulicicidum. A gene cluster, consisting of 13 genes, has been identified and biosynthetic machinery functionally characterised. This work reveals a highly complex biosynthetic array, furnishing multiple nodulisporic acid congeners. The variation arises due to the action of a single promiscuous P450 monooxygenase, NodJ.
Indole terpenoids make up a large group of secondary metabolites that display an enticing array of bioactivities. While indole diterpene (IDT) and rarely indole sesquiterpene (IST) pathways have been ...found individually in filamentous fungi, here we show that both cluster types are encoded within the genome of Tolypocladium album. Through heterologous reconstruction, we demonstrate the SES cluster encodes for IST biosynthesis and can tailor IDT substrates produced by the TER cluster.
The significant structural diversity and potent bioactivity of the fungal indole diterpenes (IDTs) has attracted considerable interest in their biosynthesis. Although substantial skeletal diversity ...is generated by the action of noncanonical terpene cyclases, comparatively little is known about these enzymes, particularly those involved in the generation of the subgroup containing emindole SA and DA, which show alternate terpenoid skeletons. Here, we describe the IDT biosynthetic machinery generating these unusual IDT architectures from Aspergillus striatus and Aspergillus desertorum. The function of four putative cyclases was interrogated via heterologous expression. Two specific cyclases were identified that catalyze the formation of epimers emindole SA and DA from A. striatus and A. desertorum, respectively. These cyclases are both clustered along with all the elements required for basic IDT biosynthesis yet catalyze an unusual Markovnikov-like cyclization cascade with alternate stereochemical control. Their identification reveals that these alternate architectures are not generated by mechanistically sloppy or promiscuous enzymes, but by cyclases capable of delivering precise regio- and stereospecificities.
Nodulisporic acids (NAs) are structurally complex potent antiinsectan indole diterpenes. We previously reported the biosynthetic gene cluster for these metabolites in Hypoxylon pulicicidum and ...functionally characterised the first five steps of the biosynthetic pathway. Here we reveal a highly complex biosynthetic array, furnishing multiple end products through expression of cluster components in Penicillium paxilli. We show that seven additional cluster‐encoded gene products comprise the biosynthetic machinery that elaborate precursor NAF in this highly branched pathway. The combined action of these enzymes delivers 37 NA congeners including four major end products, NAA, NAA1, NAA2 and NAA4. The plethora of intermediates arises due to modification of the carboxylated prenyl tail by a single promiscuous P450 monooxygenase, NodJ, a pivotal branchpoint enzyme which produces four distinct biosynthetic products giving rise to the complex metabolic grid that characterises NA biosynthesis.
Nodulisporic acids are structurally complex potent antiinsectan natural products produced by the filamentous fungus Hypoxylon pulicicidum. A gene cluster, consisting of 13 genes, has been identified and biosynthetic machinery functionally characterised. This work reveals a highly complex biosynthetic array, furnishing multiple nodulisporic acid congeners. The variation arises due to the action of a single promiscuous P450 monooxygenase, NodJ.
During the 2021 Heat Dome, 619 people in British Columbia died due to the heat. This public health disaster was made worse by the ongoing COVID-19 pandemic. Few studies have explored the intersection ...of heat with COVID-19, and none in Canada. Considering that climate change is expected to increase the frequency of extreme heat events, it is important to improve our understanding of intersecting public health crises. Thus, this study aimed to explore media-based public health communication in Canada during the COVID-19 pandemic and the 2021 Heat Dome. A qualitative content analysis was conducted on a subset of media articles (n = 520) related to the COVID-19 pandemic which were identified through a previous media analysis on the 2021 Heat Dome (n = 2909). Many of the articles provided conflicting health messages that may have confused the public about which health protective actions to take. The articles also showed how the COVID-19 pandemic may have exacerbated the health impacts of the 2021 Heat Dome, as pandemic-related public health measures may have deterred people away from protecting themselves from heat. This study, which provides novel insight into the prioritization of public health messaging when an extreme heat event occurs concurrently with a pandemic, supports the need for consistent heat health guidance.
During extreme heat events (EHEs) the public often learns about health protective actions through the media. Visual news coverage can act as a powerful tool to help convey complex health protective ...actions to the public. Despite the importance of images in helping the public understand the risk, there has been no systematic analysis to assess what images have been used by media outlets in Canada during EHEs. This paper helps to fill that gap by analyzing how the Canadian media visually communicated the risks of extreme heat to the public during the unprecedented 2021 Heat Dome. A review of thousands of online news media articles published about the 2021 Heat Dome in Canada was conducted on five subscription news databases. Overall, 845 images were coded to identify denotative, connotative, and ideological content. Only 16% of these published images implied that heat was dangerous, of which only 40% depicted people, and 46% implied human suffering. Our findings demonstrate that the majority of images used in Canadian news coverage on the 2021 Heat Dome are incompatible with, and frequently contradict, evidence-based heat protective actions. Governments, public health agencies, and other stakeholders engaged in distributing heat preparedness messaging (e.g., journalists) should prioritize improving the images of extreme heat in news coverage to align with evidence-based public health messages. With rising global temperatures due to climate change and the associated increases in the frequency and intensity of extreme heat events, prioritizing these actions is critically important to offset the threat posed to public health.
We examined demographic, clinical, and psychological characteristics of a large cohort (n = 368) of adults with dissociative seizures (DS) recruited to the CODES randomised controlled trial (RCT) and ...explored differences associated with age at onset of DS, gender, and DS semiology.
Prior to randomisation within the CODES RCT, we collected demographic and clinical data on 368 participants. We assessed psychiatric comorbidity using the Mini-International Neuropsychiatric Interview (M.I.N.I.) and a screening measure of personality disorder and measured anxiety, depression, psychological distress, somatic symptom burden, emotional expression, functional impact of DS, avoidance behaviour, and quality of life. We undertook comparisons based on reported age at DS onset (<40 v. ⩾40), gender (male v. female), and DS semiology (predominantly hyperkinetic v. hypokinetic).
Our cohort was predominantly female (72%) and characterised by high levels of socio-economic deprivation. Two-thirds had predominantly hyperkinetic DS. Of the total, 69% had ⩾1 comorbid M.I.N.I. diagnosis (median number = 2), with agoraphobia being the most common concurrent diagnosis. Clinical levels of distress were reported by 86% and characteristics associated with maladaptive personality traits by 60%. Moderate-to-severe functional impairment, high levels of somatic symptoms, and impaired quality of life were also reported. Women had a younger age at DS onset than men.
Our study highlights the burden of psychopathology and socio-economic deprivation in a large, heterogeneous cohort of patients with DS. The lack of clear differences based on gender, DS semiology and age at onset suggests these factors do not add substantially to the heterogeneity of the cohort.
PDF
