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Combining SAXS analysis and MD simulation to determine structure and hydration of ionizable lipid hexagonal phases
Get PDFCationic ionizable lipids (CILs) are fundamental components of inverse hexagonal (HII) lipid assemblies, which mediate the encapsulation and release of negatively charged mRNA through a pH-dependent mechanism. Since variations in the structure and composition of the HII phases can significantly impact the biological efficacy of the mRNA-carrying lipid nanoparticles (LNP), a comprehensive understanding of the ionizable lipid HII phases is necessary. We present an integrated approach combining small-angle X-ray scattering (SAXS) experiments, molecular dynamics (MD) simulations and a continuum model to elucidate lipid distribution and water content within HII phases. Our results indicate strong agreement between structures derived from MD simulations and SAXS data. To this end, we introduce a method to correct for periodic boundary artifacts when computing scattering profiles from MD simulations. This enables direct, model-free comparisons between experimental and simulated data, enhancing the reliability of structural interpretations, specifically the water content of the HII phases. Next, we developed a continuum model to extend structural analysis to CIL HII phases for which MD data is unavailable. This integrative framework not only provides molecular-level insights into the ionizable lipid HII mesophase but also enables the prediction of hydration properties across different CIL compositions. The different approaches consistently yield water contents that seem to correlate with the lipids’ transfection efficiencies. By bridging experimental and simulation data, our approach offers a powerful tool for the rational design and optimization of lipid nanoparticles, potentially linking a lower water content with an increased therapeutic performance
Effects of adopting voice assistants countermeasures on alerting drowsy drivers across age
Get PDFDrowsy driving is one of the leading contributing factors to traffic accidents. As drivers continue driving despite being aware of their drowsy states, it is necessary to adopt active countermeasures to avoid them falling asleep behind the wheel. Based on the multiple resources model, this study proposed five countermeasure types using voice assistants (no-countermeasure vs. meaninglessly listening vs. meaningfully listening vs. repeating vs. answering) and investigated their effects on countering drowsiness for young and middle-aged drivers. A five-week simulated manual driving experiment was conducted to evaluate the effectiveness of countermeasures based on driver performance, physiological indicators, eye movement indicators, and subjective ratings. Results indicated that repeating and answering were the two most effective countermeasures. The self-reported sleepiness of these two countermeasures (6.328 and 5.276 for repeating and answering, respectively) were significantly (p < 0.05) lower than that of the no-countermeasure (7.983). The physiological arousal state in term of skin conductance level for the two (1.798 and 1.990 for repeating and answering, respectively) were significantly (p < 0.05) higher than that of the no-countermeasure (1.022). Consistent patterns were also found in driving performance, eye movement indicators, psychomotor vigilance task accuracy, and subjective acceptance ratings. These findings suggested that countermeasures involving more resource stages can enhance drivers’ alertness. The trend of higher alertness in the answering condition compared to the repeating condition highlighted the advantage of increasing cognitive load in countering drowsiness. Although young and middle-aged drowsy drivers did not differ on their average responses to different countermeasures, they showed differences in their physiological activation in reacting to the countermeasures. Drowsiness countermeasures should be tailored to fulfill individual needs, particularly for middle-aged drivers. This study not only clarifies how drowsiness countermeasures work but also offers practical guidance for vehicle designers on using in-vehicle voice assistants effectively
HIV status and the risk of typhoid fever and iNTS: a systematic review and meta-analysis
Get PDFObjectives: The WHO recommends prioritising people living with HIV (PLHIV) for typhoid vaccination, but evidence for increased typhoid fever risk is inconsistent. We aimed to evaluate whether HIV infection alters the risk of blood culture-confirmed typhoid fever.
Methods: We systematically searched four databases from inception to 30 November 2023 for studies reporting Salmonella Typhi bacteraemia with documented HIV status. Where available, we also extracted data on invasive non-typhoidal Salmonella (iNTS) bacteraemia. We used random-effects meta-analysis to pool odds ratios (ORs) and assessed effect modification by ART era, age, and CD4 count.
Results: Seventeen studies met inclusion criteria, comprising 10,117 PLHIV and 53,289 HIV-negative individuals from Africa and Asia. PLHIV had lower odds of typhoid fever (OR 0.53, 95% CI 0.30–0.92), but higher odds of iNTS disease (OR 4.06, 2.23–7.39). Apparent protection against typhoid was most evident in adults with CD4 counts <200 cells/µl and was not significant after ART rollout.
Conclusions: Advanced HIV infection may reduce the risk of typhoid fever. While altered clinical presentations or healthcare-seeking behaviours could contribute, the contrasting increase in iNTS risk within the same populations suggests a genuine difference in susceptibility. These findings support re-evaluating WHO guidance that prioritises PLHIV for typhoid vaccination
From mitochondrial DNA arrangement to repair:a kinetoplast-associated protein with different roles in two trypanosomatid species
Get PDFBACKGROUND: One of the most intriguing and unusual features of trypanosomatids is their mitochondrial DNA, known as kinetoplast DNA (kDNA), which is organized into a network of concatenated circles. The kDNA is contained within the mitochondrial matrix and can exhibit distinct arrangements across different species and during cell differentiation. In addition to kDNA, the kinetoplast contains multiple proteins, including those involved in mitochondrial DNA topology and metabolism, such as the kinetoplast-associated proteins (KAPs). In this work, we obtained mutant cells to investigates the role of KAP7 in two trypanosomatid species, Trypanosoma cruzi and Angomonas deanei, which have distinct kinetoplast shapes and kDNA arrangements. METHODS: For this purpose, the kDNA replication process and cell morphology and ultrastructure were evaluated using microscopy methods. Furthermore, the proliferation of cells treated with genotoxic agents, such as cisplatin and ultraviolet radiation, was analyzed. RESULTS: In A. deanei, which contains a symbiotic bacterium, KAP7 seems to be essential, since the deletion of one KAP7 allele generated mutants with a decay in cell proliferation, as well as changes in kDNA structure and replication. In T. cruzi, null mutants exhibited disturbances in kDNA replication, although the overall topology remained unaltered. The use of cisplatin and ultraviolet (UV) radiation affected the ultrastructure of A. deanei and T. cruzi. Cisplatin promoted increased kDNA compaction in both KAP7 mutants, but only in T. cruzi did the proliferative capacity fail to recover after treatment, as was also observed following UV radiation exposure. CONCLUSIONS: Proteins associated with DNA are evolutionarily conserved and usually perform similar functions in different organisms. Our findings reveal that KAP7 is involved in kDNA replication, but its roles differ in trypanosomatid species: in A. deanei, KAP7 is associated with kDNA arrangement, while in T. cruzi, it is related to mitochondrial metabolism, such as kDNA replication and damage response
Supporting the professional development of trial managers: how can you help?
Get PDFClinical trial managers are central to the successful design and delivery of clinical trials, making them crucial within the research landscape. Yet, despite their vital contribution, many trial managers report feeling undervalued, under-supported, and insufficiently recognised for the expertise they bring to their teams. Unlike other research roles, there is no clearly defined career pathway for trial managers, and opportunities for professional growth are often limited. In the UK, those working on academic-led trials are usually employed within universities or NHS trusts, frequently based in UKCRC-registered Clinical Trial Units. In this article, we provide practical guidance for both trial managers and their employers on how to strengthen professional development opportunities and better support this essential workforce
New insights into combined thermal and vibration softening of magnesium alloy in rotational vibration assisted incremental sheet forming
Get PDFWith the generation of both localised thermal and vibration in incremental sheet forming (ISF) by novel tool designs, rotational vibration assisted ISF (RV-ISF) can achieve significant force reduction and material softening. However, the combined thermal and vibration softening in RV-ISF is unclear. By evaluating the similarities and differences of friction stir ISF (FS-ISF) and RV-ISF, this study develops a novel approach to decouple and quantify the thermal and vibration softening effects in RV-ISF of AZ31B-H24, providing new insights into underlying thermal and vibration softening mechanism. Experimental results reveal that in RV-ISF of AZ31B-H24 the thermal softening due to frictional heating dominates with 45 ∼ 65 % of softening, while the vibration effect only contributes up to 15 % of softening, from the conventional ISF, depending on the tool designs and tool rotational speed. The double-offset tool (T2) produces greater vibration softening than the three-groove tool (T3) owing to the higher vibration amplitude of the T2 tool. An increase in tool rotational speed primarily enhances thermal softening with only marginal changes to the vibration effect. Microstructural analysis suggests that with average grain size of 0.94 µm at the top layer, RV-ISF with T3 and 3000 rpm is more effective for microstructure refinement than that by FS-ISF, especially on the tool-sheet contact surface, which confirms the occurrence of surface shearing. This refinement is a result of the reduced recrystallisation degree, 71.8 % at the top bottom layer. Compared with FS-ISF, RV-ISF can lead to not only higher geometrically necessary dislocation density, but also higher fraction of low-angle grain boundaries, indicating that softening mechanism due to localised vibration effect is resulted from the enhanced rearrangement and annihilation of dislocations. These findings contribute to new understanding of the thermal and vibration softening effects in RV-ISF of AZ31B-H24 and offer a theoretical foundation for the tool design and process optimisation
High-resolution Staphylococcus profiling reveals intra-species diversity in a single skin niche
Get PDFThe skin microbiome is dominated by a few key genera, among which Staphylococcus is one of the most well characterized. Recent studies have examined the roles of various Staphylococcus species such as Staphylococcus epidermidis and Staphylococcus hominis within broader skin microbial communities. However, these investigations often rely on isolates from multiple individuals and hence limit their ability to capture intra-community interactions. In this study, we focused on the axillary microbiome of a single healthy individual to characterize the genetic and functional diversity of resident Staphylococcus isolates. Using a low-cost, high-throughput DNA extraction and long-read whole-genome sequencing pipeline, we generated complete genomes for 93 isolates spanning 7 genetically distinct lineages across 3 major skin species. These comprised one dominant and three additional lineages of S. epidermidis, two of S. hominis and one of Staphylococcus capitis. Functional and metabolic analyses revealed species- and strain-specific features, suggesting potential metabolic cross-feeding and specialization within this community, including within strains of S. epidermidis. These findings highlight the metabolic complexity and potential interdependence of staphylococci inhabiting a single skin site and the need for strain-level resolution of the community. The strains form part of the York Skin Microbiome (YSM) collection, a growing open biobank of genetically diverse skin isolates from matched individuals
Whose needs are met? Navigating tensions in academic language support at a Vietnamese EMI university
Get PDFIn keeping with the marked expansion of English-medium instruction (EMI) in Asian contexts, this study offers detailed evaluation of academic language support for EMI courses in a Vietnamese university. It explores academic language needs and current provision of support and challenges through the perceptions of multiple stakeholder groups: students, language instructors and content lecturers. Data was obtained from 10 semi-structured interviews with teaching staff and a questionnaire involving 175 students. Survey data was processed using descriptive statistics and inferential statistics while interview data was analysed using thematic analysis. The findings indicated a general alignment between teachers’ and students’ views on students’ current abilities, but a divergence in their perceptions of target academic language needs. Moreover, language and content teachers were found to offer support mostly in areas of writing and reading, and their focus was on either teaching generic skills or assisting content comprehension, respectively, rather than catering to subject-specific language as desired by students. Key challenges to their support were identified, including students’ limited English proficiency and motivation, coordination issues and time constraints. Finally, practical implications regarding teachers’ pedagogical roles and professional development, as well as institutional guidance in the implementation of language support in EMI contexts, were discussed
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