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A collaboration between the University of Oxford and Thailand’s Mahidol University has been shortlisted for the prestigious 2017 Newton Prize for its project aiming to understand the early stages of scrub typhus in Thailand.
Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption.
The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in RNU4-2, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in RNU4-2 and 21 individuals with de novo and/or recurrent variants in RNU5B-1 and RNU5A-1, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. RNU4-2 variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5' splice site recognition and associate with different phenotypic severity. RNU4-2 variants result in specific defects in alternative 5' splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes RNU5B-1 as a neurodevelopmental disorder gene, suggests RNU5A-1 as a strong candidate and highlights the role of de novo variants in snRNAs.
'Treat-to-target': a call for earlier targeted intervention in asthma.
The treat-to-target (TTT) approach is a concept that has been successfully implemented in many disease areas, such as rheumatoid arthritis (RA) and cardiovascular disease, and is more recently being discussed in asthma. Currently, asthma management is focused on severity of symptoms and disease control, with treatment approaches tailored to these symptoms versus the underlying disease activity. Although successful in many patients, there are limitations to this approach, as treatments targeting the underlying pathophysiology of disease may not be initiated until later on a patient's disease trajectory. This can leave patients with uncontrolled asthma despite high treatment doses, or initiating these treatments after long-term lung-function decline has already occurred. Implementing a TTT approach in asthma that focuses on remission as a treatment goal advocates for a more personalised treatment approach whereby the remission target offers patients and clinicians a clear benchmark for the best possible outcomes, and treatments that target the underlying pathophysiology of disease are initiated earlier in the disease course, to optimise long-term outcomes and prevent irreversible lung-function decline.
Placental and Cord Blood DNA Methylation Changes Associated With Gestational Diabetes Mellitus in a Marginalized Population: The Untold Role of Saturated Fats.
The role of DNA methylation (DNAm) and its modulation by dietary factors in gestational diabetes mellitus (GDM) remains underexplored, particularly in marginalized populations. This study investigates DNAm alterations in GDM-exposed cord blood and placenta and their association with maternal dietary quality and single nutrient intake in a low-income population from the Myanmar-Thailand border. A matched case-control design (GDM: n = 38, controls: n = 34) was selected from a Myanmar-Thailand pregnancy cohort. Dietary intake was assessed via 24-h recalls and analyzed using Nutritionist Pro, with dietary quality evaluated by the healthy eating index (HEI). DNAm was profiled in 72 cord blood and 72 placental samples using the Infinium MethylationEPIC array. Significant differences in dietary vitamin D, total folate, and saturated fat intake were observed between the groups. RnBeads analyses revealed hypomethylation as the predominant DNAm pattern in GDM, particularly at ADORA2B (placenta) and ZFP57 (cord blood) promoters. The excessive intake of saturated fats was associated with GDM hypomethylation profiles and negatively correlated with ZFP57 methylation levels. This study highlights the influence of saturated fat intake on epigenetic changes in pregnancy, revealing potential biomarkers for GDM and emphasizing the need for tailored, population-specific nutritional interventions to mitigate transgenerational health impacts.
Shear-Dependent Platelet Aggregation by ChAdOx1 nCoV-19 Vaccine: A Novel Biophysical Mechanism for Arterial Thrombosis.
Rare thrombotic events associated with ChAdOx1 nCoV-19 (ChAdOx1) vaccination have raised concerns; however, the underlying mechanisms remain elusive. Here we report a novel biophysical mechanism by which ChAdOx1 directly interacts with platelets under arterial shear conditions, potentially contributing to post-vaccination arterial thrombosis. Using microfluidic post assays, we demonstrate that ChAdOx1 induces shear-dependent platelet aggregation, distinct from conventional von Willebrand factor-mediated adhesion. This interaction is mediated by platelet integrin αIIbβ3 and requires biomechanical activation, explaining the absence of significant binding under static conditions. Molecular dynamics simulations and docking studies reveal preferential binding of ChAdOx1's penton RGD motif to the activated conformation of αIIbβ3. Inhibiting integrin αIIbβ3 completely abolishes ChAdOx1-induced platelet aggregation, whereas blocking GPIb has minimal effect, confirming a mechanism that bypasses the conventional GPIb-dependent platelet adhesion pathway. Mutagenesis of the RGD motif to AAA eliminates platelet binding, verifying the specificity of this interaction. These findings provide a potential explanation for the association between ChAdOx1 vaccination and arterial thrombotic events, distinct from vaccine-induced immune thrombotic thrombocytopenia (VITT). Our results highlight the importance of considering biomechanical factors in vaccine-related thrombotic complications and suggest that shear-dependent integrin activation may be another determinant in the pathogenesis of these rare adverse events.
Identifying context-specific determinants to inform improvement of antimicrobial stewardship implementation in healthcare facilities in Asia: results from a scoping review and web-based survey among local experts.
International guidelines are available for the assessment and improvement of antimicrobial stewardship (AMS) programmes: an important strategy to address the escalating global antimicrobial resistance problem. However, existing AMS assessment tools lack contextual specificity for resource-limited settings, leading to limited applicability in Asia. This project aimed to identify relevant themes from current guidance documents to help develop a context-specific assessment tool that can be applied by healthcare facilities (HCFs) to improve local implementation.We performed a sequential approach of a scoping review to identify relevant assessment themes for Asia and an expert survey for getting feedback on the relevance of assessment stems developed from the scoping review. We reviewed English-language published documents discussing AMS implementation or assessment at HCFs globally and in Asia. Themes were derived through content analysis and classified following the predefined context dimensions to develop assessment stems, defined as containing one identified determinant that may influence implementation outcomes. The survey consisting of identified assessment stems was reviewed by 20 locally identified experts in Asia who rated the level of relevance of these stems in AMS implementation in the region.National leadership, training and technical support, and policy and guidance were the most commonly identified themes among 100 themes identified from 73 reviewed documents. From these themes, we developed 131 assessment stems for the expert survey. Of the 131 assessment stems, 117 (89%) were considered relevant for AMS implementation in Asia by at least 80% of respondents. These stems were included in the process of developing a global AMS assessment tool to support HCFs to improve their programmes.In conclusion, national leadership and support represent a distinct and important aspect affecting AMS implementation in HCFs in Asia. The identified assessment themes have substantial value for the formulation of locally relevant implementation strategies tailored to the Asian context.
Small-molecule dissolution of stress granules by redox modulation benefits ALS models.
Neurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.
In-cell chromatin structure by Cryo-FIB and Cryo-ET.
Chromatin, the complex of DNA and proteins that organises genetic material in eukaryotic cells, has been a focal point of biological research for over a century. Its structure determines critical functions such as gene regulation, DNA replication and chromosome segregation. Early models of chromatin were limited by technological constraints, but advancements in imaging, particularly X-ray and electron microscopy (EM), gradually unveiled its hierarchical organisation. The recent emergence of cryo-electron tomography (cryo-ET) coupled with cryo-focused ion beam (cryo-FIB) milling has revolutionised our understanding of chromatin organisation by providing native, three-dimensional (3D) views of various macromolecules and architectures of chromatin at unprecedented resolution. This review traces the historical progression of chromatin structural studies, from early EM and fluorescence microscopy to the transformative insights offered by cryo-ET, culminating in a synthesis of current knowledge and future directions.
BactiVac, the Bacterial Vaccines Network.
Bacterial vaccines save lives and constitute a major tool to address the challenge of anti-microbial resistance, though, despite their success, there is a relative paucity of such vaccines. Historically there has not been a network that focuses on bacterial vaccines, to promote sharing of approaches and best practices, and provide advocacy. BactiVac, the Bacterial Vaccines Network, was established in August 2017 to address this gap. Its mission is to advance vaccine development against global bacterial infections in humans and animals, to reduce disease, death, and antimicrobial resistance, and thereby enhance economic development. BactiVac brings together academia, industry, policymakers and funders from high-income countries (HICs) and low- and middle-income countries (LMICs), in a network of 2060 members from 92 countries, including 51 % from LMICs and 15 % from industry. BactiVac supports vaccine development through Catalyst Project Awards and Catalyst Training Awards. This funding targets bottlenecks and capacity-building in vaccinology, particularly among LMIC early-career researchers. Annual Network Meetings facilitate exchange of information and ideas, and new collaborations. We provide advocacy for bacterial vaccines nationally and internationally and, by partnering with aligned networks, function as a network within a network of networks. Therefore, through providing financial support and facilitating collaboration, BactiVac supports and enhances the bacterial vaccinology community to help reduce the devastating burden of disease caused by bacterial infections.
Disease outbreak data to inform decision-making: the role of disease spread models in the Lao P.D.R. African Swine Fever epidemic, 2019.
Understanding the spread of African Swine Fever (ASF) between villages in the southeast-Asian, low - middle income country context is critical if this high impact disease is to be controlled by good policy and effective field activities in these resource-poor settings. Using governmental reporting data from the 2019 outbreak of ASF in Lao People's Democratic Republic, spatial clustering techniques were used to identify clusters of outbreak villages. Then Approximate Bayesian Computation with Sequential Monte Carlo was used to estimate the transmission parameters of ASF virus between the villages within these clusters. We used a simple disease spread model to understand the impact of parameter estimation on predicted disease spread and thus decision-making. Six clusters of radius 16 to 153km were identified over the 7 month outbreak period. Within these clusters, the basic reproduction number (R0) ranged from 13 to 32 between-villages and whole-village infectious periods ranged from 62 to 68 days. The final model outputs were compared to the original field report data. We found that the ability of the estimated parameters to match field data was heavily reliant on how the original field surveillance data was reported. Specifically, in situations in which cases in a cluster appeared to have been reported as batches (lack of temporal specificity) our modelling approach failed to produce satisfactory outputs in terms of model fit and precision of estimates. This study demonstrates that surveillance for transboundary diseases not only has immediate benefit for disease response, but that good quality surveillance data is valuable for informing future planning for disease response via appropriately parameterised disease spread models. There is a need for ongoing quality control of surveillance and support for field veterinary services to ensure quality data that can be used to drive policy and decision-making.
Exploring patients’ and carers’ experiences, understandings and expectations of COPD exacerbations:an interview study
BackgroundChronic obstructive pulmonary disease (COPD) exacerbations are clinically significant events that affect millions of people globally.AimTo explore patients’ and carers’ experiences, understanding, and expectations of, as well as their responses to, exacerbations.Design & settingSemi-structured interviews conducted with patients who have COPD and their carers from four sites across England.MethodInterviews were conducted with a purposive sample of patients with COPD and their carers recruited from four sites in England: two in Yorkshire, one in Hampshire and one in London. Interviews were theoretically informed by the Breathing Space concept and analysed using reflexive thematic analysis. This research is reported in line with the Standards for Reporting Qualitative Research.ResultsForty patient participants were recruited: 21 were female, 28 were White, with a mean age 69 years (standard deviation [SD] = 8.1 years), mean COPD duration = 11.3 years (SD = 8.3 years), median exacerbations in past year = 1.5 (range 0–9). Seven carer participants were recruited; of these, six were female and six were White. Three themes were identified: the language that clinicians use in COPD is important; episodes of symptom worsening have profound impacts on patients and carers; and patients’ early experiences, including the responses of clinicians to their help-seeking, have a lasting effect on their behaviour. How patients respond to symptom worsening can be considered holistically in the context of the Breathing Space framework. Breathlessness affected all patient participants and was a key symptom that precipitated action.ConclusionsOur findings show how early help-seeking experiences shape later behaviour. Early emphasis on symptom management, preparation for exacerbations, and post-exacerbation reviews are practical ways that clinicians can support patients and carers to manage these events better. The Breathing Space concept provides a useful framework to identify needs and tailor COPD management appropriately.
Longer-term virologic outcomes on tenofovir-lamivudine-dolutegravir in second-line ART
Background: Dolutegravir in second-line antiretroviral therapy (ART) is more effective with recycled tenofovir than switching to zidovudine. However, dolutegravir resistance is more frequent in second-line compared to first-line ART.Objectives: We report long-term virologic outcomes from a clinical trial.Method: AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST) was a randomised, double-blind, phase II clinical trial. Eligible participants had two consecutive HIV-1 RNA ≥ 1000 copies/mL on first-line ART, mostly tenofovir-emtricitabine-efavirenz. Participants were switched to tenofovir-lamivudine-dolutegravir (TLD) with lead-in 50 mg dolutegravir twice daily in stage one (n = 62), and randomised to TLD with additional lead-in 50 mg dolutegravir or placebo for the first 14 days in stage two (n = 130). We present results up to 158 weeks, combining stages one and two.Results: We enrolled 192 participants: 127/176 (72%) had resistance (Stanford score ≥ 15) to both tenofovir and lamivudine. At week 48, 151/186 (81%; 95% confidence interval [CI] 75%, 87%) had HIV-1 RNA 50 copies/mL. Of 127 participants with follow-up through week 158, 78% (95% CI 70%, 85%) maintained HIV-1 RNA 50 copies/mL, 11% had HIV-1 RNA 50–999 copies/mL, and 11% had HIV-1 RNA ≥ 1000 copies/mL. Twenty-nine participants met criteria for resistance testing: one developed intermediate-level dolutegravir resistance (G118R mutation) at week 96, and one had high-level dolutegravir resistance (E138K, G118R, G163R, T66A mutations) detected at week 146.Conclusion: Among adults switching to TLD with detectable HIV-1 RNA and substantial tenofovir and lamivudine resistance, a high proportion maintained virologic suppression up to 158 weeks. Emergent dolutegravir resistance occurred in ~1% of participants after 2–3 years on second-line TLD.
Implementation strategies to improve outcomes in patients with established cardiovascular disease in sub-Saharan Africa: A systematic review.
The protocol was registered in PROSPERO prior to the study implementation (ID: CRD42023465781). The protocol can be accessed at crd.york.ac.uk/PROSPERO/display_record.php?RecordID=465781.