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Decoding receptor selection and specificity in Class 3 Semaphorins
No full textRobust control over axon navigation is crucial for the development of a healthy, functional nervous system, and is partially afforded by Semaphorins. Their jurisdiction is not confined to axon guidance either, with diverse contributions to synaptogenesis, dendritic spine regulation, and even vascular repair depending on the given receptor. Precise selection of receptor complexes enables targeted activation of desired signalling pathways and firm control of downstream biological outcomes, however the source of Sema receptor specificity is elusive. As such, the determinants of Sema3 recognition of Neuropilin, Plexin and auxiliary L1-IgCAM receptors were sought, through the lens of Sema3G, Nrp2 and PlxnA4/D1, in the following thesis.
Structural and biophysical examination of Sema3G homo-dimerisation and assembly with Nrp2 culminated in an unprecedented hetero-oligomeric array rich in atypical contacts and compelling insights into Sema3 receptor recognition. Further, mutagenesis of a targeted Sema loop revealed a short motif exclusive to Sema3G vital for associating with Nrp2, but not Nrp1. Manifold efforts to optimise Sema3G complexation with Nrp2/Plxn holoreceptor complexes enabled the preparation of pure samples for structural studies, but were ultimately unable to capture the elusive Plexin. Crystal structures of the first four and first six NrCAM Ig domains revealed Ig1-4 ‘horseshoe’ architectures and homo-dimerisation modes evocative of related L1-IgCAMs, however attempts to situate NrCAM in Sema3/Nrp signalling were foiled by unsuccessful Sema3F/Nrp2 and NrCAM/Nrp2 complexation, poor expression of the cognate PlxnA3 receptor and dubious structural predictions. Nonetheless, these persistent bids built the foundations for impending studies targeting co-receptor assembly with Plxns and IgCAMs.
Enriching the current understanding of class 3 Semaphorin receptor complex assembly, the following thesis demonstrates a novel mechanism of Sema-Nrp oligomerisation and bestows notable advances in decoding Nrp specificity
Exploring auditory morphodynamics: Audiovisual associations in sound-based music
Get PDFThis article explores audiovisual associations within the context of contemporary and experimental music practices, particularly focusing on sound-based music. While extensive studies exist on crossmodality in relation to traditional music genres (such as classical instrumental music), the perceptual potential of sound-based music remains an underexplored field of psychological research. In an online procedure, 152 participants were exposed to six musical excerpts from spectralism and electronic-glitch music and were asked to rate the extent to which each audio matched with six ad hoc generated black and white abstract images. Statistical analysis revealed that ratings were highly consistent across participants, indicating that they may rely on a shared set of implicit perceptual criteria rooted in Gestalt and morphodynamic features common to both auditory and visual stimuli. In particular, smoothness, continuity, numericity, symmetry, and spectrotemporal dimensions emerged as the primary factors influencing the association ratings. We discuss the implication of these findings both for crossmodal research and musicology, and suggest some directions for future research in audiovisual associations using sound-based music
Relationships between Polycyclic Aromatic Hydrocarbons, Small Dust Grains, H 2, and H i in Local Group Dwarf Galaxies NGC 6822 and WLM Using JWST, ALMA, and the VLA
Get PDFWe present 0.6–3.2 pc resolution mid-infrared (MIR) JWST images at 7.7 μm (F770W) and 21 μm (F2100W) covering the main star-forming regions of two of the closest star-forming low-metallicity dwarf galaxies, NGC 6822 and Wolf–Lundmark–Melotte (WLM). The images of NGC 6822 reveal filaments, edge-brightened bubbles, diffuse emission, and a plethora of point sources. By contrast, most of the MIR emission in WLM is pointlike, with a small amount of extended emission. Compared to solar-metallicity galaxies, the ratio of 7.7 μm intensity ( IνF770W ), tracing polycyclic aromatic hydrocarbons (PAHs), to 21 μm intensity ( IνF2100W ), tracing small, warm dust grain emission, is suppressed in these low-metallicity dwarfs. Using Atacama Large Millimeter/submillimeter Array CO(2–1) observations, we find that detected CO intensity versus IνF770W at ≈2 pc resolution in dwarfs follows a similar relationship to that at solar metallicity and lower resolution, while the CO versus IνF2100W relationship in dwarfs lies significantly below that derived from solar-metallicity galaxies at lower resolution, suggesting more pronounced destruction of CO molecules at low metallicity. Finally, adding in Local Group L-Band Survey 21 cm H i observations from the Very Large Array, we find that IνF2100W and IνF770W versus total gas ratios are suppressed in NGC 6822 and WLM compared to solar-metallicity galaxies. In agreement with dust models, the level of suppression appears to be at least partly accounted for by the reduced galaxy-averaged dust-to-gas and PAH-to-dust mass ratios in the dwarfs. Remaining differences are likely due to spatial variations in dust model parameters, which should be an exciting direction for future work in local dwarf galaxies
Prevalence and progress of underdiagnosis of probable dementia: a repeated cross-sectional study in 19 European countries
Get PDFBackground: Underdiagnosis of dementia remains a significant public health challenge in Europe, with nearly half of those meeting clinical criteria not receiving a formal diagnosis. Recent healthcare initiatives have aimed to improve diagnostic processes, but the extent of progress varies across countries. Methods: We analyzed data of 10,402 participants from the Survey of Health, Ageing, and Retirement in Europe (SHARE) across 19 countries from 2011–2015 to 2015–2019. Underdiagnosis of probable dementia was defined as probable dementia (based on cognition score) without a confirmed diagnosis. Weighted logistic regression was conducted to examine temporal trends in underdiagnosis of probable dementia and to identify individual- and country-level predictors of progress in diagnosis. Results: A significant reduction in underdiagnosis of dementia was observed between the two periods, consistent across most countries. Progress in diagnosis was modified by country-level factors such as number of psychiatrists, formal long-term care worker at home or institutions, and positron emission tomography and individual-level factors including age, education, retirement status, nursing home residency, multimorbidity, and healthcare utilization patterns. Conclusions: The decreasing trend in underdiagnosis highlights the importance of targeted interventions including investment in psychiatric care services. Understanding remaining disparities is crucial for informing health policies and addressing inequalities to dementia diagnosis and care
Directional white-light emission from sintered carbon dot titanium dioxide structures based on near-field confinement
Get PDFDirectional light source not only helps to advance scientific progresses but also has great potentials in many application fields. However, it is still challenging to achieve the directional white light without optical elements. Here, we report a highly directional white-light emitter driven by 1064 nm near-infrared laser with 1/60 solid angle that does not require the introduction of optical elements. The emitter which consists of binary components, i.e. carbon dot and titanium oxide, possesses a microlens-shape surface formed during the synthesis process. Upon near-infrared light excitation, carbon dot emits white light based on a fundamentally different mechanism, which may involve a process similar to bremsstrahlung, multiphoton and thermal processes. The emitted white light is then regulated in the near field by the microlens-shape surface due to the confinement effect, resulting in the high directionality. The highly directional white-light emitter exhibits excellent stability and repeatability, making it promising for applications including targeted illumination and projection
Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight
Get PDFDengue is a mosquito-borne virus infection affecting half of the world’s population for which therapies are lacking. The role of T and NK-cells in protection/immunopathogenesis remains unclear for dengue. We performed a longitudinal phenotypic, functional and transcriptional analyses of T and NK-cells in 124 dengue patients using flow cytometry and single-cell RNA-sequencing. We show that T/NK-cell signatures early in infection discriminate patients who develop severe dengue (SD) from those who do not. These signatures are exacerbated in patients with overweight/obesity compared to healthy weight patients, supporting their increased susceptibility to SD. In SD, CD4+/CD8+ T-cells and NK-cells display increased co-inhibitory receptor expression and decreased cytotoxic potential compared to non-SD. Using transcriptional and proteomics approaches we show decreased type-I Interferon responses in SD, suggesting defective innate immunity may underlie NK/T-cell dysfunction. We propose that dysfunctional T and NK-cell signatures underpin dengue pathogenesis and may represent novel targets for immunomodulatory therapy in dengue
Fragility Fracture Network Position on Unrestricted Weight-Bearing After Hip Fracture Surgery
Get PDFObjectives: This position paper from the Fragility Fracture Network (FFN) responds to the observed global variation in weight-bearing prescriptions after hip fracture surgery in older adults. Methods: The paper summarises current guidelines and evidence regarding unrestricted weight-bearing after hip fracture surgery. Results: The synthesis of available evidence supports the endorsement of unrestricted weight-bearing after surgery to enhance patient outcomes. Conclusion: The FFN endorses unrestricted weight-bearing and recommends healthcare professionals, institutions, and policymakers re-evaluate practices favouring limited or non-weight-bearing prescriptions and establish a standardised system for monitoring and auditing, with clear justification and documentation of any restrictions
Ox-LDL induces a non-inflammatory response enriched for coronary artery disease risk in human endothelial cells
Get PDFOxidised low-density lipoprotein cholesterol (ox-LDL) is critical in the initiation and progression of atherosclerosis. While excessive atherogenic lipids in the arterial intima can trigger endothelial dysfunction in advanced lesions, the response of endothelial cells to ox-LDL in the early stages of atherogenesis remains unclear. Here, we conducted a comprehensive, genome-wide multi-omics characterisation of the cellular response to ox-LDL in primary human aortic endothelial cells (HAECs). Our results reveal that the exposure of HAECs to ox-LDL leads to pathogenic changes in metabolism, transcriptome and epigenome, but in the absence of a typical inflammatory endothelial phenotype. An integrative analysis implicates the role of AP-1, NFE-2 and CEBP transcription factors in regulating ox-LDL-induced transcription. We further demonstrate that ox-LDL activates endothelial cell migration through the epigenomic rewiring of transcription factor binding. Notably, these ox-LDL-induced dynamic binding sites are enriched for the genetic risk of coronary artery disease, enabling the discovery of the gene-environment interaction of rs62172376 and ox-LDL at the CALCRL/TFPI locus. Collectively, our findings provide an unbiased understanding of the transcriptional regulation in endothelial cells in response to ox-LDL, together with its interaction with the genetic element of coronary artery disease
Digital parenting program for migrant Chinese families: a quasi-experimental study
Get PDFPurpose: This study aimed to evaluate the effectiveness of a self-directed online program, Parenting for Lifelong Health for Young Children (PLH-YC), in enhancing positive parenting practices among migrant families in China.
Methods: A quasi-experimental design was employed, with 67 parents of children aged 2–9 years assigned to either an intervention group (n = 24) or a control group (n = 43). Both qualitative and quantitative data were collected.
Results: Parents in the intervention group showed significant improvements in proactive parenting strategies and parent–child relationships compared to those in the control group. However, the intervention had no significant impact on child maltreatment, externalizing behaviors, or other parenting outcomes. Qualitative assessment revealed themes including adopting positive parenting practices, enhancing parental mental health, and promoting desired parenting outcomes.
Conclusion: The self-directed online PLH-YC program demonstrates its potential as a scalable, low-cost solution for disadvantaged parents in low- and middle-income countries
Imposter Participants in Synchronous Qualitative Research: A Systematic Scoping Review
Get PDFAlthough the issue of bots and fraudulent participants is well established within quantitative research, in recent years there have been increasing incidences of imposter participants within qualitative research. However, how qualitative researchers conceptualise this challenge and what the perceived impact of these imposter participants are, remains underexplored. This systematic scoping review identified 15 articles published since 2018 addressing the topic of imposter participants and fraudulent data in synchronous qualitative research. The review identified that the majority of current articles are commentaries or case study narratives, with little apparent inter disciplinary engagement. Findings indicate that where recommendations are offered these can be subjective or influenced by discipline, with a lack of an evidence informed approach being adopted. The analysis identified three primary issues for applied qualitative research fields, with threats to data integrity and reliability, threats to research diversity, accessibility and reach, and questions of trust and ethics within research highlighted. Developing evidence-based guidance and ensuring cross-disciplinary engagement will be central to maintaining the relevance, impact, and validity of applied qualitative research