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Functional genomics implicates ebony in the black pupae phenotype of tephritid fruit flies
No full textThe remarkable diversity of insect pigmentation offers a captivating avenue for studying evolution and genetics. In tephritids, understanding the molecular basis of mutant traits is also crucial for applied entomology, enabling the creation of genetic sexing strains through genome editing, thus facilitating sex-sorting before sterile insect releases. Here, we present evidence from classical and modern genetics showing that the black pupae (bp) phenotype in the GUA10 strain of Anastrepha ludens is caused by a large deletion at the ebony locus, removing the gene's entire coding region. Targeted knockout of ebony induced analogous bp phenotypes across six major tephritid agricultural pests, demonstrating that disruption of Ebony alone is sufficient to produce the mutant trait in distantly related species. This functional characterization further allowed a deeper exploration of Ebony's role in pigmentation and development across life stages in diverse species. Our findings offer key insights for molecular engineering of sexing strains based on the bp marker and for future evolutionary developmental biology studies in tephritids
Qualitative Exploration of Health Care Professionals’ Experiences Caring for Young People With Acute Severe Behavioral Disturbance in the Acute Care Setting
No full textOBJECTIVES: To describe the experience of health care professionals involved in the care of young people with acute severe behavioral disturbance across the acute care setting. METHODS: We used purposive and snowball sampling to recruit paramedics, nurses, doctors, and mental health clinicians caring for young people with acute severe behavioral disturbance in the prehospital and/or emergency department environments. We conducted one-to-one telephone-based semistructured qualitative interviews with each staff member. The audio recordings were transcribed verbatim, and participant pseudonyms were assigned. We iteratively developed a thematic coding structure. Data collection continued until thematic saturation was reached. RESULTS: We interviewed 31 health care professionals-12 doctors, 5 nurses, 7 mental health clinicians, and 7 paramedics. Participants outlined factors they felt contributed to the young person's behavioral disturbance. They detailed the management strategies used. Participants spoke about their exposure to physical violence while managing these young people and the challenges of balancing patient and staff safety. There was a significant personal impact on participants through providing care to this cohort. Participants acknowledged the workflow, staff resource, and bystander impacts of these presentations. CONCLUSION: Based on participant's experiences, health care staff aim to provide high-quality care to young people with behavioral disturbance in circumstances that present risks to their safety. There is variability in the way staff are currently managing these young people likely because of the limited high-quality evidence currently available, highlighting key areas for future research
Metasurfaces for infrared multi-modal microscopy
No full textImaging techniques, such as bright field and phase contrast microscopy, are useful tools for analyzing information about various samples carried by light. However, they typically rely on bulky and expensive microscopes that limits their portability. Optical metasurfaces offer a compact alternative and here, we present a Mie-resonant silicon metasurface capable of switching between non-computational phase contrast and bright field imaging by changing the polarization of the illumination. We experimentally demonstrate it on biological samples of C. elegans. The metasurface has the potential for use in portable devices for point-of-care applications
Increased SARS-CoV-2 IgG4 has variable consequences dependent upon Fc function, Fc receptor polymorphism, and viral variant
No full textRepeated mRNA COVID-19 vaccination increases spike-specific immunoglobulin G4 (IgG4) titers. Here, we characterized the influence of increased IgG4 titers on a range of Fc-mediated responses. Elevated spike-specific IgG4 reduced binding to FcγRIIIa and decreased antibody-dependent cellular cytotoxicity. However, in individuals with lower total spike-specific IgG, IgG4 acted in synergy with other IgG subclasses to improve FcγRI and FcγRIIa binding and consequently antibody-dependent cellular phagocytosis. Furthermore, this trend was more pronounced with more recent SARS-CoV-2 variants where vaccination induced comparably lower total spike-specific titers. These observations were further confirmed by in silico modeling where antibody subclass concentrations and FcγR polymorphisms were modulated. Collectively, we illustrate that the impact of elevated IgG4 titers upon Fc functions is dependent on multiple interconnected antibody and antigen factors, which should be taken into consideration when dissecting the mechanisms driving an effective Fc-mediated response following vaccination
Retinal Disease Variability in Female Carriers of RPGR Variants Associated with Retinitis Pigmentosa: Clinical and Genetic Parameters
No full textObjectives: We sought to investigate the visual function, retinal features, and genotype–phenotype correlations of an Australian cohort of RPGR carriers. Methods: In this cross-sectional study, we evaluated RPGR carriers seen in Melbourne and Perth between 2013 and 2023 and healthy women seen between 2022 and 2023 in Melbourne. Visual acuity tests, fundus-tracked microperimetry, and retinal imaging were performed. RPGR carriers were classified into four retinal phenotypes (normal, radial, focal pigmentary retinopathy, and male pattern phenotype) and compared against healthy controls. Genotype–phenotype relationships in the RPGR carriers were investigated. Results: Thirty-five female RPGR carriers and thirty healthy controls were included in this study. The median ages were 40 and 48.5 years for RPGR carriers and controls, respectively (p = 0.26). Most RPGR carriers (89%) had a genetic diagnosis. Best-corrected visual acuity (BCVA), low luminance visual acuity, retinal sensitivity, central inner retinal thickness (IRT, 1°), and photoreceptor complex (PRC) thickness across the central 1–7° of the retina differed between phenotypes of RPGR carriers. On average, RPGR carriers with ORF15 variants (n = 25 carriers) had reduced LLVA, a greater IRT at 1°, and thinner PRC thickness at 7° from the fovea (all p < 0.05) compared to those with exon 1–14 variants. Conclusions: Female RPGR carriers with severe retinal phenotypes had significantly decreased visual function and changes in retinal structure in comparison to both the controls and carriers with mild retinal disease. BCVA, LLVA, retinal sensitivity, and retinal thickness are biomarkers for detecting retinal disease in RPGR carriers. The genetic variant alone did not influence retinal phenotype; however, RPGR carriers with ORF15 variants exhibited reduced retinal and visual measurements compared to those with exon 1–14 variants
Structural plasticity of the coiled–coil interactions in human SFPQ
No full textThe proteins SFPQ (splicing Factor Proline/Glutamine rich) and NONO (non-POU domain-containing octamer-binding protein) are mammalian members of the Drosophila Behaviour/Human Splicing (DBHS) protein family, which share 76% sequence identity in their conserved 320 amino acid DBHS domain. SFPQ and NONO are involved in all steps of post-transcriptional regulation and are primarily located in mammalian paraspeckles: liquid phase-separated, ribonucleoprotein sub-nuclear bodies templated by NEAT1 long non-coding RNA. A combination of structured and low-complexity regions provide polyvalent interaction interfaces that facilitate homo- and heterodimerisation, polymerisation, interactions with oligonucleotides, mRNA, long non-coding RNA, and liquid phase-separation, all of which have been implicated in cellular homeostasis and neurological diseases including neuroblastoma. The strength and competition of these interaction modes define the ability of DBHS proteins to dissociate from paraspeckles to fulfil functional roles throughout the nucleus or the cytoplasm. In this study, we define and dissect the coiled-coil interactions which promote the polymerisation of DBHS proteins, using a crystal structure of an SFPQ/NONO heterodimer which reveals a flexible coiled-coil interaction interface which differs from previous studies. We support this through extensive solution small-angle X-ray scattering experiments using a panel of SFPQ/NONO heterodimer variants which are capable of tetramerisation to varying extents. The QM mutant displayed a negligible amount of tetramerisation (quadruple loss of function coiled-coil mutant L535A/L539A/L546A/M549A), the Charged Single Alpha Helix (ΔCSAH) variant displayed a dimer-tetramer equilibrium interaction, and the disulfide-forming variant displayed constitutive tetramerisation (R542C which mimics the pathological Drosophila nonAdiss allele). We demonstrate that newly characterised coiled-coil interfaces play a role in the polymerisation of DBHS proteins in addition to the previously described canonical coiled-coil interface. The detail of these interactions provides insight into a process critical for the assembly of paraspeckles as well as the behaviour of SFPQ as a transcription factor, and general multipurpose auxiliary protein with functions essential to mammalian life. Our understanding of the coiled coil behaviour of SFPQ also enhances the explanatory power of mutations (often disease-associated) observed in the DBHS family, potentially allowing for the development of future medical options such as targeted gene therapy
SmartSense-D: A safety, feasibility, and acceptability pilot study of digital phenotyping in young people with major depressive disorder
No full textBACKGROUND: Digital assessment of behaviours, including physical activity, sleep, and social interactions could be associated with changes in mood and other mental health symptoms. This study assessed the safety, feasibility, acceptability, and potential predictive value of passive and active sensing in young people with major depressive disorder (MDD). METHODS: Over eight weeks, passive (smartphone sensing, actigraphy) and active (ecological momentary assessment; EMA) data were collected from 40 young participants with MDD (aged 16-25 years). We assessed the safety, feasibility, and acceptability of daily active and passive sensing in this population. Additionally, linear mixed models and correlation analysis explored associations between passive and active sensing measures. RESULTS: Of the 48 young participants, 83% (n = 40) completed the full protocol. No adverse events were reported. Over eight weeks, participants averaged 35.9 days (65.3%) with EMAs and 37.9 days (69%) with actigraphy data. Smartphone sensors recorded communication for 21.1 days (38.4%), location for 43.1 days (78.4%), maximum unlock duration for 43.4 days (79%), social media use for 34.8 days (63.3%), and inter-key delay for 32.8 days (59.6%). Regarding acceptability, 83.1% found the application usable and comfortable. Secondary measures showed significant correlations between sleep and physical activity, and between location and phone use sensors. There was a significant negative association between daily positive mood ratings and QIDS total scores (Beta coefficient [95% CI]: 2.66 [-3.98, -1.34]; p = 0.002). CONCLUSION: Passive and active sensing methods were safe, and acceptable among young people with MDD
Identifying heterogeneity of treatment effect for antibiotic duration in bloodstream infection: an exploratory post-hoc analysis of the BALANCE randomised clinical trial
No full textBackground: The BALANCE trial demonstrated non-inferiority of 7 (vs 14) day antibiotic durations in patients with uncomplicated non-S. aureus/lugdunensis bacterial bloodstream infections (BSI). However, there may be patient subgroups who benefit from longer durations. We aimed to evaluate if bedside clinical decision rules could identify these subgroups. Methods: In this post-hoc analysis of the multicentre, randomised BALANCE trial (October 17, 2014–May 5, 2023), we applied three clinical decision rules to investigate heterogeneity of treatment effect in 7-day vs 14-day antibiotic durations on 90-day all-cause mortality. We used the rules to categorize patients in BALANCE into different risk groups and calculated the unadjusted absolute risk difference (RD) for 90-day mortality in patients receiving 7- vs 14-day antibiotics within each risk group. Statistical significance was tested using an interaction test. The BALANCE trial is registered with ClinicalTrials.gov (NCT03005145). Findings: 3581 patients were included. All three rules predicted mortality risk, but none identified statistically significant effect modification: (a) static rule (low-risk: RD −0.58, 95% CI −8.91 to 7.73; moderate-risk: RD −.01, 95% CI −3.86 to 1.83; high-risk: RD −2.65, 95% CI −7.12 to 1.81; p = 0.74); (b) dynamic rule (met rule on day 7: RD −2.18, 95% CI −4.81 to 0.45; did not meet rule: RD 1.75, 95% CI −3.89 to 7.40; p = 0.16); and (c) early clinical failure criteria (score<2: RD −2.38, 95% CI −5.0 to 0.23; score ≥2: RD −0.65, 95% CI −5.06 to 3.77; p = 0.24). Results were consistent across sensitivity analyses including imputation for missing data and restricting analyses to gram-negative BSI. Interpretation: The decision rules included in our analyses did not identify a subgroup of patients within BALANCE that would benefit from 14 (vs 7) days of treatment. 7-day treatment duration is sufficient for most patients with uncomplicated non-S. aureus/lugdunensis BSI. Future research could explore data-driven machine-learning approaches to identify comprehensive combinations of patient characteristics that may guide individualised duration of antibiotic therapy. Funding: The BALANCE trial was funded by the Canadian Institutes of Health Research, Health Research Council of New Zealand, Australian National Medical Research Council, Physicians Services Incorporated Ontario and Ontario Ministry of Health and Long-term Care Innovation Fund. SWXO conducted this study as part of his PhD studies, with funding from: the Emerging & Pandemic Infections Consortium (University of Toronto, Canada); Connaught International Scholarship (University of Toronto, Canada); the Queen Elizabeth II Graduate Scholarship in Science and Technology (QEII-GSST; Government of Ontario, Canada); and the Melbourne Research Scholarship (University of Melbourne, Australia). VML is supported by Clinical Research Scholar—Junior 2 program (FRQ-S)
The fourth-stage autoinfective larva of Strongyloides stercoralis: redescription and diagnostic implications
No full textHuman strongyloidiasis is often underdiagnosed or misdiagnosed, which can relate to a lack of knowledge or recognition of the importance of particular developmental/larval stages of Strongyloides stercoralis in making an accurate diagnosis using parasitological methods (a morphological approach or morphological features/characters). Here, we report the identification of S. stercoralis autoinfective fourth-stage larvae (L4a) in naturally infected humans, encountered in two clinical cases in Australia. These larvae were identified in sputum (Case 1) and bronchoalveolar lavage (Case 2) specimens by direct wet-mount microscopy. The L4a of S. stercoralis can be morphologically differentiated from autoinfective third-stage larvae by its conical and pointed tail and a relatively mature genital primordium with an enlarged genital rudiment and the formation of a vulva within cuticle layers. This study emphasizes the need to consider these morphological features of the L4a stage for an accurate diagnosis of S. stercoralis infection. A detailed morphological description of this stage is given to guide laboratory practitioners and researchers in the identification and differentiation of this unique but neglected life-cycle stage of S. stercoralis
Energy-based modelling of single actin filament polymerization using bond graphs
No full textBond graphs provide an energy-based methodology for modelling complex systems hierarchically; at the moment, the method allows biological systems with both chemical and electrical subsystems to be modelled. Herein, the bond graph approach is extended to include chemomechanical transduction thus extending the range of biological systems to be modelled. Actin filament polymerization and force generation is used as an example of chemomechanical transduction, and it is shown that the TF (transformer) bond graph component provides a practical, and conceptually simple, alternative to the Brownian ratchet approach of Peskin, Odell, Oster and Mogilner. Furthermore, it is shown that the bond graph approach leads to the same equation as the Brownian ratchet approach in the simplest case. The approach is illustrated by showing that flexibility and non-normal incidence can be modelled by simply adding additional bond graph components and that compliance leads to non-convexity of the force-velocity curve. Energy flows are fundamental to life; for this reason, the energy-based approach is utilized to investigate the power transmission by the actin filament and its corresponding efficiency. The bond graph model is fitted to experimental data by adjusting the model physical parameters