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Study protocol: Australasian Registry of Severe Cutaneous Adverse Reactions (AUS-SCAR)
Get PDFIntroduction Severe cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand.
Methods and analysis Adult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data.
Ethics and dissemination This study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences
Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning
Get PDFUnderstanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes
Yarning circles providing support for Aboriginal Australians after acquired brain injury
No full textAims: Building on previous research into culturally secure services, this paper reports on the development and progress of the first support groups specifically for Aboriginal people with brain injury and their families. Based in Western Australia, the groups are designed to encourage social and emotional well-being and improve health outcomes for this population. This presentation includes discussion of barriers and facilitators to establishment of the support groups.
Methods: Support groups known as ‘yarning circles’ led by Aboriginal facilitators were established within one regional and one metropolitan area. They are held both ‘on-country’ and in community centres that have close connections with local Aboriginal communities. They offer culturally secure psycho-social support, education, practical problem-solving, yarning and socialization. A participatory action research methodology is monitoring the development and outcomes over six months. Qualitative and quantitative methods are being used to assess feasibility, acceptability and effectiveness of the group intervention. Ten Aboriginal people ⩾18 years, post either stroke or traumatic brain injury and their family members/carers will be recruited at each site.
Results: Completed to date: Aboriginal research engagement and ethics approvals; appointment of an Aboriginal Project Manager and two trained Aboriginal group facilitators; commencement of yarning circles in each region; ongoing marketing of the groups via social media, circulation of flyers to Aboriginal corporations, hospitals and brain injury services. Assessments and interviews with the facilitators and Aboriginal participants are ongoing.
Conclusions: This co-designed study embeds knowledge transfer and sustainability in the development of the support groups. The study will document strategies, challenges and facilitators involved in the establishment of such groups and will inform the feasibility of future culturally secure implementation of brain injury yarning circles in metropolitan and regional/remote areas across the state and nationally
Association of jasmonic acid priming with multiple defense mechanisms in wheat plants under high salt stress
Get PDFSalinity is a global conundrum that negatively affects various biometrics of agricultural crops. Jasmonic acid (JA) is a phytohormone that reinforces multilayered defense strategies against abiotic stress, including salinity. This study investigated the effect of JA (60 μM) on two wheat cultivars, namely ZM9 and YM25, exposed to NaCl (14.50 dSm−1) during two consecutive growing seasons. Morphologically, plants primed with JA enhanced the vegetative growth and yield components. The improvement of growth by JA priming is associated with increased photosynthetic pigments, stomatal conductance, intercellular CO2, maximal photosystem II efficiency, and transpiration rate of the stressed plants. Furthermore, wheat cultivars primed with JA showed a reduction in the swelling of the chloroplast, recovery of the disintegrated thylakoids grana, and increased plastoglobuli numbers compared to saline-treated plants. JA prevented dehydration of leaves by increasing relative water content and water use efficiency via reducing water and osmotic potential using proline as an osmoticum. There was a reduction in sodium (Na+) and increased potassium (K+) contents, indicating a significant role of JA priming in ionic homeostasis, which was associated with induction of the transporters, viz., SOS1, NHX2, and HVP1. Exogenously applied JA mitigated the inhibitory effect of salt stress in plants by increasing the endogenous levels of cytokinins and indole acetic acid, and reducing the abscisic acid (ABA) contents. In addition, the oxidative stress caused by increasing hydrogen peroxide in salt-stressed plants was restrained by JA, which was associated with increased α-tocopherol, phenolics, and flavonoids levels and triggered the activities of superoxide dismutase and ascorbate peroxidase activity. This increase in phenolics and flavonoids could be explained by the induction of phenylalanine ammonia-lyase activity. The results suggest that JA plays a key role at the morphological, biochemical, and genetic levels of stressed and non-stressed wheat plants which is reflected in yield attributes. Hierarchical cluster analysis and principal component analyses showed that salt sensitivity was associated with the increments of Na+, hydrogen peroxide, and ABA contents. The regulatory role of JA under salinity stress was interlinked with increased JA level which consequentially improved ion transporting, osmoregulation, and antioxidant defense
Mainstreaming orphan millets for advancing climate smart agriculture to secure nutrition and health
Get PDFThe ever-changing climate and the current COVID-19 pandemic compound the problems and seriously impact agriculture production, resulting in socio-economic insecurities and imposing health implications globally. Most of the poor and malnourished population in the developing countries depends on agriculture for food, income, and employment. Impact of climate change together with the COVID-19 outbreak revealed immense problems highlighting the importance of mainstreaming climate-resilient and low input crops with more contemporary agriculture practices. Orphan millets play a vital role in the poor and malnourished population's livelihood, food and nutrition security. Recognizing their unique potential, the United Nations-Food and Agriculture Organization has announced the year 2023 as the “International Year of Millets”. However, despite the unique properties for present and future agriculture of orphan millets, their cultivation is declining in many countries. As a result, millets have gained attention from researchers which eventually decelerated “multi-omics” resource generation. This review summarizes the benefits of millets and major barriers/ bottlenecks in their improvement. We also discuss the pre- and post-harvest technologies; policies required to introduce and establish millets in mainstream agriculture. To improve and ensure the livelihood of the poor/malnourished population, intensive efforts are urgently needed in advancing the research and development, implementing pre- and post-harvest technological intervention strategies, and making favorable policies for orphan crops to accomplish food and nutrition security. National and international collaborations are also indispensable to address the uncertain effects of climate change and COVID-19
The rhetoric and reality of equitable access to higher education in the Anglophone Caribbean: Transforming vision into action
Get PDFThis study is about access to higher education (HE) in the Anglophone Caribbean. It seeks to answer two questions: what rhetoric is evident in current policies that guide access to higher education in the Anglophone Caribbean? And what is the reality of how policies and practices impact access to higher education opportunities for students? These questions are answered through an equity-focused lens. The study used a sequential mixed-method design and the research was conducted in three phases. Phase one was an analysis of extant documentation on existing policies and practices for twelve Anglophone Caribbean countries. Phase two comprised a series of interviews with government officials and higher education officers about their conceptualizations and perceptions of equitable access to HE. In phase three, an online student survey was organized to compare the experiences of students across the region in accessing HE and to examine their perceptions about the policies and practices guiding access. The findings of this research reveal a region-wide deficit in data management, program and policy implementation, and monitoring and evaluation. Additionally, the existing policy documents include mostly implicit references to equity of access to HE. Further findings reveal that while there is ample provision for HE across the region, fair access to those opportunities is still a challenge. The major barriers to access perceived by students and education officials are HE funding, HE cost and related expenses, access for persons with disabilities, and rural/remote access. Equity groups most affected are those with low socio-economic status (SES) and first generation in higher education students (FGHEs). Variables NOT perceived as barriers to HE access in the region were gender, race/ethnicity, religion, age, sexual orientation and cultural/linguistic background. These findings are discussed in the context of the Caribbean’s ongoing development
Pathogenesis and Treatment of Usher Syndrome Type IIA
Get PDFUsher syndrome (USH) is the most common form of deaf-blindness, with an estimated prevalence of 4.4 to 16.6 per 100,000 people worldwide. The most common form of USH is type IIA (USH2A), which is caused by homozygous or compound heterozygous mutations in the USH2A gene and accounts for around half of all USH cases. USH2A patients show moderate to severe hearing loss from birth, with diagnosis of retinitis pigmentosa in the second decade of life and variable vestibular involvement. Although hearing aids or cochlear implants can provide some mitigation of hearing deficits, there are currently no treatments aimed at preventing or restoring vision loss in USH2A patients. In this review, we first provide an overview of the molecular biology of the USH2A gene and its protein isoforms, which include a transmembrane protein (TM usherin) and an extracellular protein (EC usherin). The role of these proteins in the inner ear and retina and their impact on the pathogenesis of USH2A is discussed. We review animal cell-derived and patient cell-derived models currently used in USH2A research and conclude with an overview of potential treatment strategies currently in preclinical development and clinical trials
An accuracy-maximization learning framework for supervised and semi-supervised imbalanced data
No full textWhile we attempt to develop the balanced error rate (BER) minimization learning framework for randomized learning of feedforward neural networks to deal with imbalanced datasets, it remains unclear whether the BER minimization learning framework can be effectively extended into its semi-supervised version. This paper proposes a new concept of accuracy maximization for randomized learning methods on imbalanced datasets for the first time, and theoretically proves that it is equivalent to the minimization of the generalized BER for the use of the selected neural networks. In particular, accuracy maximization can be easily extended to semi-supervised scenarios as its semi-supervised version is proved to be linearly dependent on its original. In this paper, based on the proposed accuracy maximization concept, we propose an accuracy-maximization learning framework, and further develop a new accuracy-maximization extreme learning machine AMELM by taking Extreme Learning Machine (ELM) as a typical randomized learning method for feedforward neural networks so as to handle challenging data issues such as the class imbalance and label scarcity. It is worth noting that the proposed accuracy maximization based framework is not only suitable for ELM, but can be extended to different randomized learning methods, such as Random Vector Functional Link Network (RVFL), and Schmidt Neural Network (SNN) for supervised and semi-supervised imbalanced data. The efficacy of AMELM is tested on extensive benchmark datasets. Experimental results show that AMELM can achieve satisfactory performances on labeled or partially labeled imbalanced data. Also, AMELM obtains at least comparable classification performance to other baseline methods yet has fewer hyperparameters to tune, showing its potential for practical applications
A novel targeted DNA insertion system using Cpf1 and Himar transposase
Get PDFCRISPR-Cas proteins have been exploited in genome recombineering research since they can induce targeted Double Stranded Breaks (DSBs) in the DNA. This has been particularly useful since cellular repair mechanisms will resect DSBs and introduce mutations in the process. Each Cas protein has a distinct PAM recognition site which expands the range of possible DNA targets in a genome. Catalytically dead versions of CRISPR-Cas enzymes which cannot introduce a DSB but are still able to bind to DNA has facilitated studies in gene repression and regulation. A dead-Cas9 protein has been fused to the Hsmar transposase showing a proof of concept for targeted DNA insertion.
This thesis has developed novel strategies to fuse a catalytically dead dCpf1 protein to the Mariner Himar transposase producing a protein that is able to target T-rich PAM sites for targeted DNA insertion. A strategy was designed to facilitate the cloning of the fusion under the control of the inducible promoter pTet in a p15A chloramphenicol resistant backbone. In this strategy, the final plasmid carrying this fusion was designated pDHD. This construct was designed so that different guides could easily be directionally cloned into the backbone and be transcriptionally activated by T7 RNA polymerase. This feature is particularly desirable as it allows the plasmid to target many different DNA sites.
To monitor for integration into DNA a bioassay was developed. The design included the use of Escherichia coli DH5α (pDHD, pSW213 and pT7T7) grown in the presence of anhydrous tetracycline (aTc) to induce the dCpf1-Himar fusion and IPTG to induce RNA polymerase, the guide RNA for dCpf1 and lacZα. This would enable the chromosomal lacZω to be targeted by dCpf1-Himar fusion complexed to its guide to enable incorporation of the mini-Himar transposon carrying neomycin resistance at this location. This mini-Himar transposon is located within the backbone of pSAM_Rl. Since this plasmid carried an active TnpA, this gene had to be excised by restriction digestion and religated. This gene was excised in this study and the final construct was designated pSAM_RlΔTnpA. Since this plasmid contains an R6K oriV, it would need to be electroporated into E. coli DH5α (pDHD, pSW213 and pT7T7) in order to be replicated. Transformants containing mini-Himar insertions would need to be selected as neomycin resistant white colonies on plates containing neomycin, X-Gal, aTc and IPTG.
All components were prepared for the assay except for pDHD which did not contain the Cas-TnpA fusion as expected based on the restriction profile. Further work is required to ensure the correct restriction profile is established prior to performing the bioassay. An alternative strategy to produce the Cas-TnpA fusion was designed, but due to time constraints, further work is necessary to produce the final construct. Once the final Cas-TnpA construct has been developed, successful targeted transposition could be tested using the bioassay outlined in this thesis.
The development of an inducible dCpf1-Himar transposase fusion would expand the current toolset available to scientists to perform targeted DNA insertions
Episparis tortuosalis (Lepidoptera: Erebidae: Pangraptini) a new pest of Chukrasia tabularis (Meliaceae) plantations in Vietnam
No full textEpisparis tortuosalis (Moore, The Lepidoptera of Ceylon, L. Reeve Company, London, 1867) (Lepidoptera: Erebidae: Pangraptini) is a significant pest defoliating Chukrasia tabularis plantations in Vietnam. Since 2013 the geographic range of the pest has increased from one to nine provinces. Field surveys in 9 provinces in 2021 showed that feeding by E. tortuosalis larvae resulted in the damage incidence ranging from 28.5 to 100% and the damage index from 0.82 to 3.66. This study illustrates the male and female morphology and genitalia of this pest from Vietnam. Further studies are recommended to help develop an integrated pest management plan for this pest