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Multiple mechanisms of termination modulate the dynamics of RNAPI transcription
Get PDFTranscription elongation is stochastic, driven by a Brownian ratchet, making it subject to changes in velocity. On the rDNA, multiple polymerases are linked by “torsional entrainment” generated by DNA rotation. We report that release of entrainment by co-transcriptional 3′ end cleavage, is permissive for relative movement between polymerases, promoting pausing and backtracking. Subsequent termination (polymerase release) is facilitated by the 5′ exonuclease Rat1 (Xrn2) and backtracked transcript cleavage by the RNA polymerase I (RNAPI) subunit Rpa12. These activities are reproduced in vitro. Short nascent transcripts close to the transcriptional start site, combined with nascent transcript folding energy, similarly facilitate RNAPI pausing. Nascent, backtracked transcripts at pause sites are terminated by forward and reverse “torpedoes”: Rat1 and the exosome cofactor Trf4/5-Air1/2-Mtr4 polyadenylation (TRAMP), respectively. Topoisomerase 2 localizes adjacent to RNAPI pause sites, potentially allowing continued elongation by downstream polymerases. Mathematical modeling supported substantial premature termination. These basic insights into transcription in vivo will be relevant to many systems.</p
TREM2 supports neuronal protection and microglial reactivity without an effect on misfolded protein deposition in chronic neurodegenerative prion disease
Get PDFINTRODUCTION: Triggering receptor expressed on myeloid cells-2 ( TREM2) variants have been identified as risk factors for neurodegenerative disease, including Alzheimer's disease. TREM2 is a cell surface receptor on microglia that regulates homeostatic and immunomodulatory functions, including phagocytosis of apoptotic debris and the resolution of damage-associated inflammation. It remains unclear how TREM2 may mediate an influence on neurodegenerative disease, particularly in relation to key neuropathological hallmarks such as neuronal loss and proteinopathy. METHODS: We used the ME7 prion disease model to assess the role of TREM2 in the progression and pathology of neurodegenerative disease. Prion diseases are characterised by the accumulation of misfolded prion proteins and provide a highly tractable platform to determine if TREM2 has disease-modifying effects.RESULTS: Trem2 -/- and wild-type (WT) mice were inoculated intracerebrally with mouse-passaged ME7 scrapie prions, and their effects on CNS disease pathogenesis were determined. Although the accumulation of prion disease-specific PrP was similar in the brains of mice from each group, the severity of neuropathology was increased in Trem2 -/- mice. Morphometric analysis of the microglia also indicated blunted disease-induced reactivity in the brains of infected Trem2 -/- mice compared to wild-type (WT) controls. Expression of genes involved in myelination was reduced in prion-infected Trem2 -/- mice compared to infected WT mice. CONCLUSION: We conclude that during brain infection with prions, TREM2 supports microglial reactive changes associated with resilience to neuronal loss independently of affecting misfolded PrP deposition. These data imply that TREM2 status may be an important influence on the downstream response to CNS proteinopathy, which alters the susceptibility of neurons and brain tissue to proteinopathy-induced degenerative changes.</p
Integrative genomics sheds light on the immunogenetics of tuberculosis in cattle
Get PDFMycobacterium bovis causes bovine tuberculosis (bTB), an infectious disease of cattle that represents a zoonotic threat to humans. Research has shown that the peripheral blood (PB) transcriptome is perturbed during bTB disease but the genomic architecture underpinning this transcriptional response remains poorly understood. Here, we analyse PB transcriptomics data from 63 control and 60 confirmed M. bovis-infected animals and detect 2592 differently expressed genes perturbing multiple immune response pathways. Leveraging imputed genome-wide SNP data, we characterise thousands of cis-expression quantitative trait loci (eQTLs) and show that the PB transcriptome is substantially impacted by intrapopulation genomic variation during M. bovis infection. Integrating our cis-eQTL data with bTB susceptibility GWAS summary statistics, we perform a transcriptome-wide association study and identify 115 functionally relevant genes (including RGS10, GBP4, TREML2, and RELT) and provide important new omics data for understanding the host response to mycobacterial infections that cause tuberculosis in mammals
On the persistence of discourse predictions:The facilitative effect of discourse markers diminishes in the presence of intervening material
Get PDFThe current study investigates for how long readers maintain expectations about an upcoming discourse relation. We use the pair of discourse markers On the one hand (OT1H) and On the other hand (OTOH) to test the facilitative effect of OT1H on the processing of OTOH and the sensitivity of this effect to the presence of intervening material. Results from a story continuation study indicate that intervening material slightly weakens the effect of OT1H on offline representations of the discourse. Results from a self-paced reading and two eye-tracking studies suggest that the presence of intervening material diminishes the facilitative effect of OT1H in online processing. These results support memory-based models of processing by showing that discourse dependencies, while they are built as fine-grained representations, are not unbounded in real-time processing
Spatiotemporal variation in size-dependent growth rates in small isolated populations of Arctic charr (Salvelinus alpinus)
Get PDFAs a key life-history trait, growth rates are often used to measure individual performance and to inform parameters in demographic models. Furthermore, intraspecific trait variation generates diversity in nature. Therefore, partitioning out and understanding drivers of spatiotemporal variation in growth rate is of fundamental interest in ecology and evolution. However, this has rarely been attempted owing to the amount of individual-level data required through both time and space, and issues with missing data in important covariates. Here, we implemented a Bayesian state-space model using individual-level data from 20 populations of Arctic charr (Salvelinus alpinus) across 15 capture occasions, which allowed us to: (i) integrate over the uncertainty of missing recapture records; (ii) robustly estimate size-dependence; and (iii) include a covariate (water temperature) that contained missing data. Interestingly, although there was substantial spatial, temporal and spatiotemporal variation in growth rate, this was only weakly associated with variation in water temperature and almost entirely independent of size, suggesting that spatiotemporal variation in other environmental conditions affected individuals across sizes similarly. This fine-scale spatiotemporal variation emphasizes the importance of local conditions and highlights the potential for spatiotemporal variation in a size-dependent life-history trait, even when environmental conditions are apparently very similar
Assessment of the Topology and Oligomerisation States of Coiled Coils Using Metadynamics with Conformational Restraints
Get PDFCoiled-coil proteins provide an excellent scaffold for multistate de novo protein design due to their established sequence-to-structure relationships and ability to switch conformations inresponse to external stimuli, such as changes in pH or temperature. However, the computational design of multistate coiled-coil protein assemblies is challenging, as it requires accurate estimates of the free energy differences between multiple alternative coiled-coil conformations. Here, we demonstrate how this challenge can be tackled using metadynamics simulations with orientational, positional and conformational restraints. We show that, even for subtle sequence variations, our protocol can predict the preferred topology of coiled-coil dimers and trimers, the preferred oligomerization states of coiled-coil dimers, trimers, and tetramers, as well as the switching behavior of a pH-dependent multistate system. Our approach provides a method for predicting the stability of coiled-coil designs and offers a new framework for computingbinding free energies in protein−protein and multiprotein complexes
Acute LPS exposure enhances susceptibility to peripheral prion infection
Get PDFAfter peripheral infections, the initial accumulation of prions within secondary lymphoid tissues is essential for the transmission of disease to the brain. Macrophages are considered to sequester or destroy prions, but little was known of their impact on disease susceptibility after a peripheral infection. Inflammation in the peritoneal cavity can trigger the macrophage disappearance reaction, whereby the macrophages are temporarily contained within cellular aggregates on the mesothelium. We studied the impact of the bacterial lipopolysaccharide (LPS)-mediated macrophage disappearance reaction on susceptibility to an intraperitoneal prion infection. Intraperitoneal LPS injection significantly enhanced prion disease susceptibility approximately 100X when given 24-3 h before infection. The effects on disease susceptibility coincided with the reduced abundance of macrophages within the peritoneal cavity at the time of infection and the enhanced early accumulation of prions in the spleen. This suggests that the reduced recoverable abundance of macrophages in the peritoneal cavity following acute LPS-treatment, increased disease susceptibility by enhancing the initial propagation of the prions from site of exposure (peritoneal cavity) to the spleen from where they subsequently spread to the brain. Further studies may help identify novel macrophage-targeted treatments that can reduce susceptibility to peripherally acquired prion infections.</p
Spatial modelling improves genomic evaluation in Tanzanian smallholder admixed dairy cattle
Get PDFBackground: Smallholder dairy production systems in low-and middle-income countries are characterised by large phenotypic variance due to diverse environmental effects, farming practices, and crossbreeding. Furthermore, small herds, low genetic connectedness, and limited data recording challenge accurate separation of environmental and genetic effect in such settings, limiting genetic improvement. Here, we evaluated the impact of modelling spatial variation between herds to address these challenges and improve the accuracy of genomic evaluation for Tanzanian smallholder dairy cattle. Results: We analysed 19,375 test-day milk yield records of 1894 dairy cows from 1386 herds across four distinct geographical regions in Tanzania. The cows had 664,822 SNP marker genotypes after quality control and were highly admixed. We fitted a series of GBLUP models to evaluate the impact of modelling the herd effect and the spatial effect on. The herd effect was fitted as an independent random effect, while the spatial effect was fitted as a random effect with Euclidean distance-based Mat ́ern covariance function. The models were compared based on: model fit; estimates of variance components and breeding values; correlations between the estimated contribution of breeding values, herd effect, and spatial effect to phenotype values; and the accuracy of phenotype prediction in cross-validation and forward validation. The results showed large differences in milk yield between and within regions, as well as significant variation due to the spatial effect, which were not fully captured by modelling the herd effect. The results also strongly indicate that a model with just the herd effect underestimated breeding values of animals in less favourable environments and overestimated breeding values of animals in more favourable environments. Conclusions: This study demonstrated the challenge of achieving accurate genomic evaluation in smallholder settings. By leveraging spatial modelling we maximised the use of available data and improved the separation of genetic and environmental effects. Further work is required to improve smallholder genetic evaluations by understanding environmental and genetic processes that drive the large phenotypic variance in African smallholder setting. Keywords: genomic evaluation; environmental effects; spatial effects; genetic effects; Afric
Prevalence and demographics of 331 rare diseases and associated COVID-19-related mortality among 58 million individuals:a nationwide retrospective observational study
No full textBACKGROUND: The Global Burden of Disease Study has provided key evidence to inform clinicians, researchers, and policy makers across common diseases, but no similar effort with a single-study design exists for hundreds of rare diseases. Consequently, for many rare conditions there is little population-level evidence, including prevalence and clinical vulnerability, resulting in an absence of evidence-based care that was prominent during the COVID-19 pandemic. We aimed to inform rare disease care by providing key descriptors from national data and explore the impact of rare diseases during the COVID-19 pandemic.METHODS: In this nationwide retrospective observational cohort study, we used the electronic health records (EHRs) of more than 58 million people in England, linking nine National Health Service datasets spanning health-care settings for people who were alive on Jan 23, 2020. Starting with all rare diseases listed in Orphanet (an extensive online resource for rare diseases), we quality assured and filtered down to analyse 331 conditions mapped to ICD-10 or Systemized Nomenclature of Medicine-Clinical Terms that were clinically validated in our dataset. For all 331 rare diseases, we calculated population prevalences, analysed patients' clinical and demographic details, and investigated mortality with SARS-CoV-2. We assessed COVID-19-related mortality by comparing cohorts of patients for each rare disease and rare disease category with controls matched for age group, sex, ethnicity, and vaccination status, at a ratio of two controls per individual with a rare disease.FINDINGS: Of 58 162 316 individuals, we identified 894 396 with at least one rare disease and assessed COVID-19-related mortality between Sept 1, 2020, and Nov 30, 2021. We calculated reproducible estimates, adjusted for age and sex, for all 331 rare diseases, including for 186 (56·2%) conditions without existing prevalence estimates in Orphanet. 49 rare diseases were significantly more frequent in female individuals than in male individuals, and 62 were significantly more frequent in male individuals than in female individuals; 47 were significantly more frequent in Asian or British Asian individuals than in White individuals; and 22 were significantly more frequent in Black or Black British individuals than in White individuals. 37 rare diseases were significantly more frequent in the White population compared with either the Black or Asian population. 7965 (0·9%) of 894 396 patients with a rare disease died from COVID-19, compared with 141 287 (0·2%) of 58 162 316 in the full study population. In fully vaccinated individuals, the risk of COVID-19-related mortality was significantly higher for eight rare diseases, with patients with bullous pemphigoid (hazard ratio 8·07, 95% CI 3·01-21·62) being at highest risk.INTERPRETATION: Our study highlights that national-scale EHRs provide a unique resource to estimate detailed prevalence, clinical, and demographic data for rare diseases. Using COVID-19-related mortality analysis, we showed the power of large-scale EHRs in providing insights to inform public health decision making for these often neglected patient populations.FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK.</p
Rethinking the value of care:A case study of sub-micro-level co-design with Scottish care workers
No full textThe social care sector in the UK is facing a crisis, as traditional public service management methods have proven ineffective in addressing the challenges of complex care systems. This paper presents a case study that investigates the process of critically reflecting on public service design, focusing on co-creating value with care workers at the individual level. By showcasing the case process and outcomes, this paper identifies three dimensions of sub-micro-level value co-creation – perceptibility, relationality, and vitality – and highlights key design characteristics: embracing contextual uniqueness, establishing flat relations in routine interactions, and sustaining small-scale interactions to foster long-term transformation. Building on these insights, the study argues that achieving meaningful change requires not only macro-level policy reforms but also sub-micro-level shifts that recognise, acknowledge, and value the vital contributions of individual care workers to society. For these statements, flexible and responsive co-design method plays an irreplaceable role
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