Genome-wide association studies have identified over 100 genetic loci for atrial fibrillation (AF); recent work described an association between loss-of-function (LOF) variants in
and early-onset AF.
...We sought to determine the contribution of rare and common genetic variation to AF risk in the general population.
The UK Biobank is a population-based study of 500 000 individuals including a subset with genome-wide genotyping and exome sequencing. In this case-control study, we included AF cases and controls of genetically determined white-European ancestry; analyses were performed using a logistic mixed-effects model adjusting for age, sex, the first 4 principal components of ancestry, empirical relationships, and case-control imbalance. An exome-wide, gene-based burden analysis was performed to examine the relationship between AF and rare, high-confidence LOF variants in genes with ≥10 LOF carriers. A polygenic risk score for AF was estimated using the LDpred algorithm. We then compared the contribution of AF polygenic risk score and LOF variants to AF risk.
The study included 1546 AF cases and 41 593 controls. In an analysis of 9099 genes with sufficient LOF variant carriers, a significant association between AF and rare LOF variants was observed in a single gene,
(odds ratio, 2.71,
=2.50×10
). The association with AF was more significant (odds ratio, 6.15,
=3.26×10
) when restricting to LOF variants located in exons highly expressed in cardiac tissue (
). Overall, 0.44% of individuals carried
variants, of whom 14% had AF. Among individuals in the highest 0.44% of the AF polygenic risk score only 9.3% had AF. In contrast, the AF polygenic risk score explained 4.7% of the variance in AF susceptibility, while
variants only accounted for 0.2%.
Both monogenic and polygenic factors contribute to AF risk in the general population. While rare
variants confer a substantial AF penetrance, the additive effect of many common variants explains a larger proportion of genetic susceptibility to AF.
Tau aggregation into insoluble filaments is the defining pathological hallmark of tauopathies. However, it is not known what controls the formation and templated seeding of strain-specific structures ...associated with individual tauopathies. Here, we use cryo-electron microscopy (cryo-EM) to determine the structures of tau filaments from corticobasal degeneration (CBD) human brain tissue. Cryo-EM and mass spectrometry of tau filaments from CBD reveal that this conformer is heavily decorated with posttranslational modifications (PTMs), enabling us to map PTMs directly onto the structures. By comparing the structures and PTMs of tau filaments from CBD and Alzheimer’s disease, it is found that ubiquitination of tau can mediate inter-protofilament interfaces. We propose a structure-based model in which cross-talk between PTMs influences tau filament structure, contributing to the structural diversity of tauopathy strains. Our approach establishes a framework for further elucidating the relationship between the structures of polymorphic fibrils, including their PTMs, and neurodegenerative disease.
Display omitted
•Cryo-EM structures of human brain-derived tau filaments from a four-repeat tauopathy•Cryo-EM and MS of tau filaments enable PTM mapping directly onto atomic models•Comparing tauopathies reveals that ubiquitination of tau can mediate fibril diversity•Integrated structural biology elucidates principles of PTM-mediated fibril assembly
Structural and mass spectrometry-based proteomics of tau filaments, including their posttranslational modifications, from corticobasal degeneration and Alzheimer’s disease point to how cross-talk between posttranslational modifications influences fibril structure, contributing to the structural diversity of tauopathy strains.
The vaginal microbiome (VMB) is a complex microbial community that is closely tied to reproductive health. Optimal VMB communities have compositions that are commonly defined by the dominance of ...certain Lactobacillus spp. and can remain stable over time or transition to non-optimal states dominated by anaerobic bacteria and associated with bacterial vaginosis (BV). The ability to remain stable or undergo transitions suggests a system with either single (mono-stable) or multiple (multi-stable) equilibrium states, though factors that contribute to stability have been difficult to determine due to heterogeneity in microbial growth characteristics and inter-species interactions. Here, we use a computational model to determine whether differences in microbial growth and interaction parameters could alter equilibrium state accessibility and account for variability in community composition after menses and antibiotic therapies. Using a global uncertainty and sensitivity analysis that captures parameter sets sampled from a physiologically relevant range, model simulations predicted that 79.7% of microbial communities were mono-stable (gravitate to one composition type) and 20.3% were predicted to be multi-stable (can gravitate to more than one composition type, given external perturbations), which was not significantly different from observations in two clinical cohorts (HMP cohort, 75.2% and 24.8%; Gajer cohort, 78.1% and 21.9%, respectively). The model identified key microbial parameters that governed equilibrium state accessibility, such as the importance of non-optimal anaerobic bacteria interactions with Lactobacillus spp., which is largely understudied. Model predictions for composition changes after menses and antibiotics were not significantly different from those observed in clinical cohorts. Lastly, simulations were performed to illustrate how this quantitative framework can be used to gain insight into the development of new combinatorial therapies involving altered prebiotic and antibiotic dosing strategies. Altogether, dynamical models could guide development of more precise therapeutic strategies to manage BV.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Spanish Pacific designates the space Spain colonized or aspired to rule in Asia between 1521--with the arrival of Ferdinand Magellan--and 1815--the end of the Manila-Acapulco galleon trade route. ...It encompasses what we identify today as the Philippines and the Marianas, but also China, Japan, and other parts of Asia that in the Spanish imagination were extensions of its Latin American colonies. This reader provides a selection of documents relevant to the encounters and entanglements that arose in the Spanish Pacific between European, Spanish Americans, and Asians while highlighting the role of natives, mestizos, and women. A-first-of-its-kind, each of the documents in this collection was selected, translated into English, and edited by a different scholar in the field of early modern Spanish Pacific studies, who also provided commentary and bibliography.
Protein dysregulation has been characterized as the cause of pathogenesis in many different diseases. For proteins lacking easily druggable pockets or catalytically active sites, targeted protein ...degradation is an attractive therapeutic approach. While several methods for targeted protein degradation have been developed, there remains a demand for lower molecular weight molecules that promote efficient degradation of their targets. In this work, we describe the synthesis and validation of a series of heterobifunctional molecules that bind a protein of interest through a small molecule ligand while targeting them to the lysosome using a short gluten peptide that leverages the TG2/LRP-1 pathway. We demonstrate that this approach can be used to effectively endocytose and degrade representative secreted, cell surface, and transmembrane proteins, notably streptavidin, the vitamin B12 receptor, cubilin, and integrin αvβ5. Optimization of these prototypical molecules could generate pharmacologically relevant LYTAC agents.
Objectives:
This study tested the effects of emotional disclosure writing and peer helping writing in reducing psychological distress among Chinese international students. This study also examined ...whether rumination and ambivalence over emotion expression moderated the effects of emotional disclosure and peer helping writing.
Method:
One hundred forty‐four Chinese international students were randomly assigned to one of three conditions: emotional disclosure, peer helping, or neutral control writing. Participants completed two 20‐min writing sessions and questionnaires at baseline, 2‐month follow‐up, and 4‐month follow‐up.
Results:
We found no significant differences across the three writing conditions in levels of psychological distress over time. However, rumination emerged as a significant moderator in both emotional disclosure and peer helping intervention conditions. High ruminators generally experienced significant reductions in depressive symptoms, whereas low ruminators experienced increased depressive symptoms.
Conclusions:
These findings demonstrate that the benefits of writing interventions may vary as a function of rumination.
The CRISPR-Cas9 system provides a versatile toolkit for genome engineering that can introduce various DNA lesions at specific genomic locations. However, a better understanding of the nature of these ...lesions and the repair pathways engaged is critical to realizing the full potential of this technology. Here we characterize the different lesions arising from each Cas9 variant and the resulting repair pathway engagement. We demonstrate that the presence and polarity of the overhang structure is a critical determinant of double-strand break repair pathway choice. Similarly, single nicks deriving from different Cas9 variants differentially activate repair: D10A but not N863A-induced nicks are repaired by homologous recombination. Finally, we demonstrate that homologous recombination is required for repairing lesions using double-stranded, but not single-stranded DNA as a template. This detailed characterization of repair pathway choice in response to CRISPR-Cas9 enables a more deterministic approach for designing research and therapeutic genome engineering strategies.
The importance of consumers’ role in sustainable consumption is reflected in the vision of the Sustainable Development Education Panel: To educate consumers to make informed consumption decisions, to ...take responsibility for their actions and to realize the impact of consumption decisions on future generations. However, educating and informing consumers alone is unlikely to change deeply entrenched unsustainable consumption behaviour. A multi‐faceted approach is required – enforcing sustainable development initiatives through legislation, promoting corporate social responsibility programs on the part of business, and (most importantly), supporting communities that engage in sustainable consumption. This study examines the proposition that individuals who identify with their community (i.e. the residential suburb or a locality where identity is understood geographically) are more likely to engage in sustainable consumption. Specifically, it examines how consumption value (i.e. the perceived value of living in a particular residential suburb) contributes to place identity and to environmental attitudes and sustainable consumption behaviour. Structural equation modelling is used to verify the conceptual model using data from a telephone survey of 561 residents from two inner city suburbs in Auckland, New Zealand. The results support the proposition that environmental attitude and sustainable consumption behaviour is enhanced by consumption values through place identity. Residents who enjoy living in their community, value a clean and healthy environment and believe their suburbs are unique tend to develop a stronger identity with their residential suburb, and are more positive towards sustainable consumption. The results have important implications for social marketers, property marketers and city councils who strive to encourage sustainable consumption among its citizens.
This article examines the expanding global tourist trade for fictional places derived from popular narratives that are recreated for the tourist’s pleasure. Through a case study of a Harry Potter ...tour in the United Kingdom, I explore how the design of fantasy-themed ventures encourage a re-imagining of the landscape where (f)actual and imaginary geographies exist side by side. The locations function as affective, liminal spaces where the tourist anticipates and partakes in the transformation of sights/sites. Narrative and spatial engagement are crucial in producing a sense of embodied experience and an enchanted, and enchanting, reality where the realms of possibility are expanded.
PDF
