Wellcome Open Research最新文献

Background: Nutritional practices during early life are critical in shaping long-term health outcomes. Poor or inappropriate nutrition may influence adiposity gain and the overall cardiometabolic risk among children born with low birth weight. Our study investigates how early feeding patterns, the timing of adiposity rebound, and DNA methylation of key genes influence cardiometabolic health at two years in low-birth-weight children.

Methods: This study will be conducted as a longitudinal follow-up study among children with low birth weight (children born with a birth weight of less than 2500 grams). A thousand four hundred children will be recruited consecutively for this study. Birth weight, gestational age, and early neonatal and perinatal details will be collected from clinical records. Information on sociodemographic characteristics, dietary practices, and antenatal, obstetric, and postnatal histories will also be collected. The two-year follow-up assessment will include anthropometric measurements (height, weight, head circumference, chest circumference, waist circumference, and skinfold thickness) and blood pressure. Biochemical investigations will include a lipid profile, serum proteins, insulin resistance assessment, and hemoglobin levels. In addition, DNA methylation at six specific CpG sites relevant to adipogenesis and cardiometabolic health will be assessed. Left ventricular mass and ejection fraction will be evaluated using echocardiography. Carotid intima-media thickness will be measured using an appropriate ultrasound probe. The neurodevelopmental status of the children will be assessed using the Developmental Assessment Scales for Indian Infants (DASII) and Vineland Social Maturity Scale (VSMS).

Conclusions: Elucidating the impact of early life nutritional practices is vital for promoting cardiometabolic health. This understanding supports the formulation of tailored feeding interventions that are essential for safeguarding cardiovascular health in children with low birth weight.

Background: Respiratory syncytial virus (RSV) is a virus with two antigenic types, A and B, that cause significant morbidity and mortality in infants globally. A recently developed maternal vaccination based on the prefusion F protein ("RSVpreF") could have a significant impact on disease burden, if introduced globally. Whether or not the effectiveness of this vaccine is affected by circulating viral genomic variability is currently unknown.

Objectives: To examine whether the vaccine effectiveness of maternal RSVpreF administration in preventing hospitalisation in infants is affected by RSV type or lineage.

Methods: We will conduct whole genome sequencing of RSV positive samples from infants hospitalised with acute lower respiratory tract infection (ALRI) in the 2024-2025 winter season, at multiple hospitals in England and Scotland, to calculate the relative vaccine effectiveness (rVE) of maternal RSVpreF vaccination by virus type (RSV-A and RSV-B). rVE will be calculated using a case control logistic regression with adjustment by infant age and admission date; sex, socioeconomic status and hospital location will be included as potential confounders if they are associated with a >3% change in rVE. We will also perform a test negative design to examine the VE for RSV-A and RSV-B separately, using RSV-negative controls from hospitals where cases were admitted. Finally, we will compare viral lineages in vaccinated versus unvaccinated infants.

Results and conclusions: Our study will identify whether currently circulating RSV genomic variability impacts on rVE. Confirmation of the null hypothesis - that there is no impact of viral genomic variability on rVE - will provide reassurance to policymakers and public health bodies as RSVpreF is rolled out globally. Conversely, an association between RSV type or lineage and decreased vaccine effectiveness will highlight the need for the enhanced comprehensive national and global molecular surveillance of RSV.

Background: Neurological symptoms following head trauma are common; however, the cause may not always be obvious. In the absence of open wounds, fractures, or surgical interventions, infectious causes may not be considered, especially viral infections such as Herpes simplex, and investigations may not be targeted to investigate this possibility.

Case: A 39-year-old male presented with a severe headache, reduced consciousness, and confusion. Two days earlier, he had been discharged from the hospital, where he had been treated for traumatic brain injury with subarachnoid hemorrhage following a road traffic accident. Herpes simplex virus type 2 (HSV-2) was detected in the cerebrospinal fluid, confirming the diagnosis of viral meningoencephalitis. He was treated with oral aciclovir for two weeks and achieved full neurological recovery.

Conclusions: This case highlights the risk of viral reactivation following trauma, particularly head injuries. Central nervous system infections, including viral infections, should be considered in cases of delayed deterioration following trauma, likely presenting with worsening headache, drowsiness and reduced cognitive state. The optimal treatment of herpes simplex virus (HSV) encephalitis may be challenging in resource-limited settings.

Despite significant investment in High-Performance Computing (HPC) clusters by funding councils, there are still many researchers whose workflows could not benefit from the computation speed that is provided by these clusters. Reducing barriers to entry for these researchers would accelerate their scientific throughput, since they will be able to respond to results in a timely fashion, improving either their protocols or correcting any problems that might have arisen. This improves the quality of science, and therefore the return on investment, in computationally-intensive areas such as Cryogenic Electron Microscopy (cryo-EM). This paper outlines a technique, FlowCron, for users to analyse their data on a HPC facility with reduced training, increasing accessibility. FlowCron transfers the responsibilities of installation and upkeep of data processing pipelines from users to HPC project PIs and/or HPC project managers, simplifies the set up of HPC pipelines, and makes pipelines as reliable as possible once set up. The work described here has software dependencies that are common to the majority of HPC clusters. We achieve this by linking Globus and cron to produce an open-source system that requires little administrative support but provides a very easy way of running an analysis on a HPC system. The user starts the analysis through the Globus website and, when started, the data will be encrypted, uploaded to the HPC, analysed, and returned to the originating machine, along with a record of the analysis. For Globus to transfer any data to and from the HPC, appropriate user authentication is required, thus ensuring that only authorised users can send data in the HPC.

Background: Major histocompatibility class I (MHC-I, human leukocyte antigen [HLA] class I in humans) molecules present small fragments of the proteome on the cell surface for immunosurveillance, which is pivotal to control infected and malignant cells. Immunogenic peptides are generated and selected in the MHC-I antigen processing and presentation pathway. In this pathway, two homologous molecules, tapasin and TAPBPR, optimise the MHC-I peptide repertoire that is ultimately presented at the plasma membrane. Peptide exchange on HLA class I by human TAPBPR involves the flexible loop region K22-D35, with the leucine at position 30 (L30) involved in mediating peptide dissociation. However, our understanding of the exact molecular mechanisms governing TAPBPR-mediated peptide exchange on HLA class I allotypes remains incomplete.

Methods: Here, in-depth re-analyses of published immunopeptidomics datasets was used to further examine TAPBPR peptide editing activity and mechanism of action on HLA class I. The role of the TAPBPR editing loop in opening the HLA class I peptide binding groove was assessed using molecular dynamics simulations and a peptide exchange assay.

Results: We show that TAPBPR shapes the peptide repertoire on HLA-A, -B and -C allotypes. The TAPBPR editing loop was not essential to allow HLA class I to adopt an open state but did allow for the HLA-A*68:02 peptide binding groove to stay open for a sustained period. L30 in the TAPBPR editing loop was typically sufficient to mediate peptide repertoire restriction on the three HLA class I allotypes expressed by HeLa cells. TAPBPR was also able to load peptides onto HLA class I in a loop-dependent manner.

Conclusions: These results suggest that the TAPBPR editing loop is involved both in peptide filtering and loading.

We present a genome assembly from an individual Erpobdella octoculata (leeches; Annelida; Clitellata; Hirudinida; Erpobdellidae). The genome sequence has a total length of 386.12 megabases. Most of the assembly (98.81%) is scaffolded into 10 chromosomal pseudomolecules. The mitochondrial genome has also been assembled, with a length of 19.12 kilobases. Gene annotation of this assembly on Ensembl identified 19 465 protein-coding genes. This assembly was generated as part of the Darwin Tree of Life project, which produces reference genomes for eukaryotic species found in Britain and Ireland.

We present a genome assembly from an individual female Nothochrysa capitata (a black lacewing; Arthropoda; Insecta; Neuroptera; Chrysopidae). The assembly contains two haplotypes with total lengths of 688.43 megabases and 587.48 megabases. Most of haplotype 1 (78.72%) is scaffolded into 8 chromosomal pseudomolecules, including the W and Z sex chromosomes. Haplotype 2 was assembled to scaffold level. The mitochondrial genome has also been assembled, with a length of 16.43 kilobases. This assembly was generated as part of the Darwin Tree of Life project, which produces reference genomes for eukaryotic species found in Britain and Ireland.

Background: The nuclear basket is a 'fishtrap'-like structure on the nucleoplasmic face of the nuclear pore complex which has been implicated in diverse functions including RNA export, heterochromatin organisation, and mitosis. Recently, a novel component of the nuclear basket, ZC3HC1, has been described. The localisation of ZC3HC1 to nuclear pores has been reported to occur reciprocally with TPR, a major structural component of the nuclear basket.

Methods: Using siRNA-mediated knock down, immunofluorescence and RNA sequencing we compare the consequences of depleting two proteins of the nuclear pore basket - TPR and ZC3HC1.

Results: We show that in human fibroblasts, although ZC3HC1 localisation to nuclear pores is TPR-dependent, TPR remains localised to pores when ZC3HC1 is depleted. Consistent with this, during oncogene-induced senescence, knockdown of ZC3HC1 does not compromise the formation of senescence-associated heterochromatin foci or activation of the senescence-associated secretory phenotype, which are both known to depend on the presence of TPR at the nuclear basket. We demonstrate that knockdown of TPR and ZC3HC1, although partially overlapping, also have many distinct transcriptional features.

Conclusions: Our results suggest that there is limited overlap in function between these two nuclear basket proteins in human diploid fibroblasts.

Controlled human infection models offer a unique opportunity to understand infectious disease pathogenesis and have accelerated vaccine development and evaluations in malaria and typhoid. One major limitation of most CHIMs is that they are typically conducted in healthy young adults who are generally the population least affected by infectious disease, and who exhibit distinct disease profiles to more at-risk populations such as people living with HIV, young children, and older adults. However, the added value of studying these populations with high relevance is only desirable if it can be done safely, robustly and acceptably. We present a framework to guide the conduct of a controlled human infection model in people living with HIV using a case-example of an experimental human pneumococcal carriage model in a setting of high disease-burden and transmission.

We present a genome assembly from an individual female Araneus angulatus (orb-weaver spider; Arthropoda; Arachnida; Araneae; Araneidae). The assembly contains two haplotypes with total lengths of 2 980.91 megabases and 2 941.08 megabases. Most of haplotype 1 (94.74%) is scaffolded into 28 chromosomal pseudomolecules. Haplotype 2 was assembled to scaffold level. The mitochondrial genome has also been assembled, with a length of 14.53 kilobases. This assembly was generated as part of the Darwin Tree of Life project, which produces reference genomes for eukaryotic species found in Britain and Ireland.