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Hidden stitches: RNA cryptic splicing and its role in human disease
Get PDFA great majority of human genes contain introns: tracts of mostly non-functional sequence that intervene the functional exons. When intron-bearing genes are transcribed into RNA, the introns are removed from the transcript via splicing, a process controlled by a multimolecular assembly called the spliceosome.
Although splicing is generally well-regulated, the spliceosome sometimes splices RNA transcripts at sites other than their canonical exon boundaries. This “cryptic” splicing can be a random event, part of an unidentified regulatory process, the effect of a mutation, or the result of other perturbances to the spliceosome’s normal behaviour.
In this thesis, I present four reports on the mechanisms underlying certain forms of cryptic splicing. In the first report, an analysis of pathogenic pseudoexons in the DMD gene reveals that each causative mutation falls into a distinct category defined by its proximity to the pseudoexon, and that many DMD pseudoexon splice sites are actively spliced in non-mutant cells. The second report builds on this by constructing a catalogue of over 400 pseudoexon variants from across the human transcriptome and uses this dataset to propose new and revised pseudoexon mutation categories. Like the first report, this second report also finds substantial congruence between pseudoexons and active deep intronic splice sites – including several recursive splice sites – suggesting a causal link between these phenomena.
A third report explores how some cryptic exons may provide an explanatory mechanism to connect common genetic variants with their associated population phenotypes and outlines a simple method for discovering new examples.
The fourth and final report uses RNA secondary structure modelling to explain why some antisense oligonucleotides can induce partial exon skipping through cryptic splice-site activation.
Collectively, these reports present several novel insights into the causes of cryptic splicing and offer suggestions for how future research may build upon these insights
Differential effects of APOE and modifiable risk factors on hippocampal volume loss and memory decline in Aβ− and Aβ+ older adults
No full textBackground and Objectives This prospective study sought to determine the association of modifiable/nonmodifiable components included in the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score with hippocampal volume (HV) loss and episodic memory (EM) decline in cognitively normal (CN) older adults classified as brain β-amyloid (Aβ) negative (Aβ−) or positive (Aβ+).
Methods Australian Imaging, Biomarkers and Lifestyle study participants (age 58–91 years) who completed ≥2 neuropsychological assessments and a brain Aβ PET scan (n = 592) were included in this study. We computed the CAIDE risk score (age, sex, APOE ε4 status, education, hypertension, body mass index [BMI], hypercholesterolemia, physical inactivity) and a modifiable CAIDE risk score (CAIDE-MR; education, hypertension, BMI, hypercholesterolemia, physical inactivity) for each participant. Aβ+ was classified using Centiloid >25. Linear mixed models assessed interactions between each CAIDE score, Aβ group, and time on HV loss and EM decline. Age, sex, and APOE ε4 were included as separate predictors in CAIDE-MR models to assess differential associations. Exploratory analyses examined relationships between individual modifiable risk factors and outcomes in Aβ− cognitively normal (CN) adults.
Results We observed a significant Aβ group × CAIDE × time interaction on HV loss (β [SE] = –0.04 [0.01]; p < 0.000) but not EM decline (β [SE] = –2.33 [9.96]; p = 0.98). Decomposition revealed a significant CAIDE × time interaction in Aβ+ participants only. When modifiable/nonmodifiable CAIDE components were considered separately, we observed a significant Aβ group × CAIDE-MR × time interaction on EM decline only (β [SE] = 3.03 [1.18]; p = 0.01). A significant CAIDE-MR score × time interaction was observed in Aβ− participants only. Significant interactions between APOE ε4 and age × time on HV loss and EM decline were observed in both groups. Exploratory analyses in Aβ− CN participants revealed a significant interaction between BMI × time on EM decline (β [SE] = –3.30 [1.43]; p = 0.02).
Discussion These results are consistent with studies showing that increasing age and APOE ε4 are associated with increased rates of HV loss and EM decline. In Aβ− CN adults, lower prevalence of modifiable cardiovascular risk factors was associated with less HV loss and EM decline over ∼10 years, suggesting interventions to reduce modifiable cardiovascular risk factors could be beneficial in this group
FeMV is a cathepsin-dependent unique morbillivirus infecting the kidneys of domestic cats
No full textFeline morbillivirus (FeMV) is a recently discovered pathogen of domestic cats and has been classified as a morbillivirus in the Paramyxovirus family. We determined the complete sequence of FeMVUS5 directly from an FeMV-positive urine sample without virus isolation or cell passage. Sequence analysis of the viral genome revealed potential divergence from characteristics of archetypal morbilliviruses. First, the virus lacks the canonical polybasic furin cleavage signal in the fusion (F) glycoprotein. Second, conserved amino acids in the hemagglutinin (H) glycoprotein used by all other morbilliviruses for binding and/or fusion activation with the cellular receptor CD150 (signaling lymphocyte activation molecule [SLAM]/F1) are absent. We show that, despite this sequence divergence, FeMV H glycoprotein uses feline CD150 as a receptor and cannot use human CD150. We demonstrate that the protease responsible for cleaving the FeMV F glycoprotein is a cathepsin, making FeMV a unique morbillivirus and more similar to the closely related zoonotic Nipah and Hendra viruses. We developed a reverse genetics system for FeMVUS5 and generated recombinant viruses expressing Venus fluorescent protein from an additional transcription unit located either between the phospho-protein (P) and matrix (M) genes or the H and large (L) genes of the genome. We used these recombinant FeMVs to establish a natural infection and demonstrate that FeMV causes an acute morbillivirus-like disease in the cat. Virus was shed in the urine and detectable in the kidneys at later time points. This opens the door for long-term studies to address the postulated role of this morbillivirus in the development of chronic kidney disease
The effect of gut microbiota and probiotics on metabolism in fish and shrimp
Get PDFThe present paper presents an overview of the effects of gut microbiota and probiotics on lipid-, carbohydrate-, protein- and amino acid metabolism in fish and shrimp. In probiotic fish studies, the zebrafish (Danio rerio) model is the most frequently used, and probiotic administration reveals the effect on glucose homeostasis, anti-lipidemic effects and increasing short-chain fatty acids, and increased expressions of genes related to carbohydrate metabolism and innate immunity, along with down-regulation of oxidative stress-related genes. Further, improved length of the intestinal villi and expression of nutrient transporters in fish owing to probiotics exposure have been documented. The present review will present an appraisal of the effect of intestinal microbiota and probiotic administration on the metabolism of nutrients and metabolites related to stress and immunity in diverse fish- and shrimp species. Furthermore, to give the reader satisfactory information on the topics discussed, some information from endothermic animals is also presented
Tea-soybean intercropping improves tea quality and nutrition uptake by inducing changes of rhizosphere bacterial communities
Get PDFThe positive aspects of the tea plant/legume intercropping system draw attention to the Chinese tea industry for its benefit for soil fertility improvement with low fertilizer input. However, limited information exists as to the roles of intercropped legumes in the rhizosphere microbiome and tea quality. Hereby, soybean was selected as the intercropped plant to investigate its effect on bacterial communities, nutrient competition, tea plant development, and tea quality. Our data showed that intercropped soybean boosted the uptake of nitrogen in tea plants and enhanced the growth of young tea shoots. Nutrient competition for phosphorus and potassium in soil existed between soybeans and tea plants. Moreover, tea/soybean intercropping improved tea quality, manifested by a significantly increased content of non-ester type catechins (C, EGC, EC), total catechins and theanine, and decreased content of ester type catechins (EGCG). Significant differences in rhizobacterial composition were also observed under different systems. At the genus level, the relative abundance of beneficial bacteria, such as Bradyrhizobium, Saccharimonadales and Mycobacterium, was significantly increased with the intercropping system, while the relative abundance of denitrifying bacteria, Pseudogulbenkiania, was markedly decreased. Correlation analysis showed that Pseudogulbenkiania, SBR1031, and Burkholderiaceae clustered together showing a similar correlation with soil physicochemical and tea quality characteristics; however, other differential bacteria showed the opposite pattern. In conclusion, tea/soybean intercropping improves tea quality and nutrition uptake by increasing the relative abundance of beneficial rhizosphere bacteria and decreasing denitrifying bacteria. This study strengthens our understanding of how intercropping system regulate the soil bacterial community to maintain the health of soils in tea plantations and provides the basis for replacing chemical fertilizers and improving the ecosystem in tea plantations
Microencapsulated probiotic Lactiplantibacillus plantarum and/or Pediococcus acidilactici strains ameliorate diarrhoea in piglets challenged with enterotoxigenic Escherichia coli
Get PDFLactiplantibacillus plantarum (strains 22F and 25F) and Pediococcus acidilactici (strain 72N) have displayed antibacterial activity in vitro, suggesting that they could be used to support intestinal health in pigs. The aim of this study was to determine if microencapsulated probiotics could reduce the severity of infection with enterotoxigenic Escherichia coli (ETEC) in weaned pigs. Sixty healthy neonatal piglets were cross-fostered and separated into five groups. Piglets to be given the microencapsulated probiotics received these orally on days 0, 3, 6, 9, and 12. Only piglets in groups 1 and 5 did not receive probiotics: those in groups 2 and 4 received the three microencapsulated probiotic strains (multi-strain probiotic), and piglets in group 3 received microencapsulated P. acidilactici strain 72N. After weaning, the pigs in groups 3-5 were challenged with 5 mL (at 109 CFU/mL) of pathogenic ETEC strain L3.2 carrying the k88, staP, and stb virulence genes. The multi-strain probiotic enhanced the average daily gain (ADG) and feed conversion ratio (FCR) of weaned piglets after the ETEC challenge (group 4), whilst supplementing with the single-strain probiotic increased FCR (group 3). Piglets in groups 3 and 4 developed mild to moderate diarrhoea and fever. In the probiotic-fed piglets there was an increase in lactic acid bacteria count and a decrease in E. coli count in the faeces. By using real-time PCR, virulence genes were detected at lower levels in the faeces of pigs that had received the probiotic strains. Using the MILLIPLEX MAP assay, probiotic supplementation was shown to reduce pro-inflammatory cytokines (IL-1α, IL-6, IL-8, and TNFα), while group 4 had high levels of anti-inflammatory cytokine (IL-10). Challenged piglets receiving probiotics had milder intestinal lesions with better morphology, including greater villous heights and villous height per crypt depth ratios, than pigs just receiving ETEC. In conclusion, prophylactic administration of microencapsulated probiotic strains may improve outcomes in weaned pigs with colibacillosis
Racism and indigenous adolescent development: A scoping review
Get PDFPrevious studies on the impacts of racism on adolescent development have largely overlooked Indigenous youth. We conducted a scoping review of the empirical literature on racism against Indigenous adolescents to determine the nature and scope of this research and to establish associations with developmental outcomes. Our literature search resulted in 32 studies with samples from the United States, Canada, Australia and New Zealand. Studies were limited to self-reported experiences of racism and thus primarily focused on perceived discrimination. Quantitative studies found small to moderate effects of perceived discrimination on adolescent psychopathology and academic outcomes. Qualitative studies provided insight into structural forms of racism. We offer recommendations for future investigations into the impacts of overt and covert racism on Indigenous adolescents
Deep learning based classification of sheep behaviour from accelerometer data with imbalance
Get PDFClassification of sheep behaviour from a sequence of tri-axial accelerometer data has the potential to enhance sheep management. Sheep behaviour is inherently imbalanced (e.g., more ruminating than walking) resulting in underperforming classification for the minority activities which hold importance. Existing works have not addressed class imbalance and use traditional machine learning techniques, e.g., Random Forest (RF). We investigated Deep Learning (DL) models, namely, Long Short Term Memory (LSTM) and Bidirectional LSTM (BLSTM), appropriate for sequential data, from imbalanced data. Two data sets were collected in normal grazing conditions using jaw-mounted and ear-mounted sensors. Novel to this study, alongside typical single classes, e.g., walking, depending on the behaviours, data samples were labelled with compound classes, e.g., walking_grazing. The number of steps a sheep performed in the observed 10 s time window was also recorded and incorporated in the models. We designed several multi-class classification studies with imbalance being addressed using synthetic data. DL models achieved superior performance to traditional ML models, especially with augmented data (e.g., 4-Class + Steps: LSTM 88.0%, RF 82.5%). DL methods showed superior generalisability on unseen sheep (i.e., F1-score: BLSTM 0.84, LSTM 0.83, RF 0.65). LSTM, BLSTM and RF achieved sub-millisecond average inference time, making them suitable for real-time applications. The results demonstrate the effectiveness of DL models for sheep behaviour classification in grazing conditions. The results also demonstrate the DL techniques can generalise across different sheep. The study presents a strong foundation of the development of such models for real-time animal monitoring
Validating the proposed framework for visualising music mood using visual texture
No full textThere are several ways to search for songs in an online music library. A few types of visual variables to represent music information such as colour, position, shape, size, and visual texture have been explored in Music Information Retrieval (MIR). However, from a comprehensive literature review, there is no research focusing explicitly on the use of visual texture for browsing music. In this research, we define visual texture as an image of texture designed using the drawing application. In this paper, a framework for visualising music mood using visual texture is proposed. This proposed framework can be used by designers or software developers to select suitable visual elements when designing a clear and understandable visual texture to represent specific music moods in the music application. This research offers a new way of browsing digital music collection and assisting the music listener community to discover new song especially in mood category. To validate the framework, usability testing was conducted. This paper presents the process of developing and validating the proposed framework
Estimating the cost of growth in southern right whales from drone photogrammetry data and long-term sighting histories
No full textAnimal body size and growth patterns play important roles in shaping the life history of species. Baleen whales include the largest animals on the planet, with somatic growth costs expected to be substantial. We used unmanned aerial vehicle photogrammetry and long-term individual sighting histories from photo identification (1991-2019) to estimate the cost of somatic growth for southern right whales (SRWs) Eubalaena australis. A Richards length-at-age growth model was developed, based on 161 calves, 20 yearlings, 1 juvenile and 23 adults, ranging in age from newborn to 27 yr. Predicted lengths were 4.7 m at birth, 12.5 m at minimum age of first parturition (6 yr) and an asymptotic length of 14.3 m. A volume-at-age curve was estimated from the body volume versus length relationship, and converted to a mass-at-age curve, using data on body tissue composition of North Pacific right whales E. japonica (n = 13). The energetic cost of growth was estimated using published estimates of tissue lipid and protein concentrations. The cost of growth for SRWs (in MJ d-1) was 2112 at birth, 544 at 4 mo, 314 at 1 yr (~weaning age), 108 at 5 yr (minimum age of sexual maturity), 51.5 at 10 yr and 5.2 at 30 yr. The cumulative cost to age 30 was 764.3 GJ, but varied widely (458-995 GJ) depending on the tissue energy content. Our estimates represent a healthy SRW population, and provide a baseline to investigate individual and population level impacts of anthropogenic disturbance (including climate change)