Premature Ventricular Contractions During the Recovery Phase of Exercise Are Only Associated with Increased Cardiovascular Mortality when Present Together with Echocardiographic Abnormalities

Background: Premature ventricular contractions (PVCs) during the recovery of exercise stress testing are associated with increased cardiovascular mortality, but the cause remains unknown. We aimed to evaluate the association of PVCs during recovery with abnormalities on echocardiography, and to evaluate their combined prognostic performance. Methods: Echocardiographic abnormalities (reduced left ventricular (LV) ejection fraction, valvular heart disease, LV dilatation, LV hypertrophy, or increased filling pressures) and the presence of PVCs during recovery (≥1/min) were identified among patients having undergone resting echocardiography within median [interquartile range] 0 [0-2] days of an exercise stress test. The association between such changes and cardiovascular mortality was analyzed using Cox regression adjusted for age, sex, clinical and exercise variables. Results: Among included patients (n=3,106, 219 events, 7.9 [5.4-11.1] years follow-up), PVCs during recovery was found in 1,327 (43%) patients, among which prevalence of echocardiographic abnormalities was increased (58% vs. 43%, p<0.001). Overall, PVCs during recovery was associated with increased cardiovascular mortality (adjusted hazard ratio (HR) [95% confidence interval] 1.6 [1.2-2.1], p<0.001). When combined with echocardiographic abnormalities, PVCs during recovery was only associated with increased risk when such were present (adjusted HR 3.3 [2.0-5.4], p<0.001), and not when absent (adjusted HR 1.4 [0.7-2.6], p=0.26), in reference to those with neither. Conclusion: PVCs during recovery was associated with increased prevalence of echocardiographic abnormalities. Increased risk of cardiovascular mortality was observed only for subjects with PVCs if concomitant echocardiographic abnormalities were present. This provides a structural explanation for the increased long-term cardiovascular risk among patients with PVCs during recovery.

Semantic Approach for Al-Quran Knowledge Representation in Islamic Knowledge Management Framework

Using ontology data model to accurately represent Al-Quran knowledge using its inherent structure of Division (Juz), Chapter (Surah), and Verse (Ayah) should be done within the framework of the Islamic Knowledge Management (IKM). Data modelling neglecting the IKM framework would result in inaccuracy and irrelevant result in knowledge processing activities involving the Al-Quran. Many of the current approaches utilizing conventional knowledge management methods such as taxonomy, hierarchy, or tree structure are limited in the sense that they only define the concepts of knowledge without relating it to a theme that defined from corpus of Islamic knowledge. In the case of Al-Quran, a classification of themes from background knowledge are important to provide a structural explanation of the knowledge and to ensure that the results obtained from a searching function of the corpus of the knowledge will result in an accurate and appropriate meaning intended by the Islamic knowledge. The aims of this paper is to demonstrate the construction of Al-Quran ontology and elaborate the searching method for representing and retrieving the relevance and accurate verses toward the theme of Al-Quran by using the semantic-based approach. The specification of Al-Quran ontology of which the prototype application was built on has been validated by experts. The evaluation test of the Al-Quran ontology application furthermore shows high precision result from searching functions done. With a good level of accuracy achieved from the test, it is hopeful that Al-Quran ontology application will provide a new experience of Al-Quran themes searching and browsing within the IKM framework for the Al-Quran readers. A capability to efficiently and accurately performing search of Al-Quran will certainly improve their understanding of Al-Quran contents.

Cellular electron tomography of the apical complex in the apicomplexan parasite Eimeria tenella shows a highly organised gateway for regulated secretion.

The apical complex of apicomplexan parasites is essential for host cell invasion and intracellular survival and as the site of regulated exocytosis from specialised secretory organelles called rhoptries and micronemes. Despite its importance, there is little data on the three-dimensional organisation and quantification of these organelles within the apical complex or how they are trafficked to this specialised region of plasma membrane for exocytosis. In coccidian apicomplexans there is an additional tubulin-containing hollow barrel structure, the conoid, which provides a structural gateway for this specialised secretion. Using a combination of cellular electron tomography and serial block face-scanning electron microscopy (SBF-SEM) we have reconstructed the entire apical end of Eimeria tenella sporozoites. We discovered that conoid fibre number varied, but there was a fixed spacing between fibres, leading to conoids of different sizes. Associated apical structures varied in size to accommodate a larger or smaller conoid diameter. However, the number of subpellicular microtubules on the apical polar ring surrounding the conoid did not vary, suggesting a control of apical complex size. We quantified the number and location of rhoptries and micronemes within cells and show a highly organised gateway for trafficking and docking of rhoptries, micronemes and vesicles within the conoid around a set of intra-conoidal microtubules. Finally, we provide ultrastructural evidence for fusion of rhoptries directly through the parasite plasma membrane early in infection and the presence of a pore in the parasitophorous vacuole membrane, providing a structural explanation for how rhoptry proteins (ROPs) may be trafficked between the parasite and the host cytoplasm

Radical epistemology, structural explanations, and epistemic weaponry

When is a belief justified? There are three families of arguments we typically use to support different accounts of justification: (1) arguments from our intuitive responses to vignettes that involve the concept; (2) arguments from the theoretical role we would like the concept to play in epistemology; and (3) arguments from the practical, moral, and political uses to which we wish to put the concept. I focus particularly on the third sort (3), and specifically on arguments of this sort offered by Clayton Littlejohn in Justification and the Truth-Connection (Oxford University Press, Oxford, 2012) and Amia Srinivasan in ‘Radical Externalism’ (Philos Rev 129(3): 395–431, 2018) in favour of externalism. I counter Srinivasan’s argument in two ways: (a) first, I show that the internalist’s concept of justification might figure just as easily in the sorts of structural explanation Srinivasan thinks our political goals require us to give; and (b) I argue that the internalist’s concept is needed for a particular political task, namely, to help us build more effective defences against what I call epistemic weapons. I conclude that we should adopt an Alstonian pluralism about the concept of justification.

“Our Side of the Story”: The Political Memoirs of the Rudd-Gillard Labor Cabinet

Political memoirs and autobiographies are an increasingly prolific form of political and historiographical communication. Few attempts have been made to explain why Australian politicians have written these books, beyond the observation that they can be self-serving narratives. This paper identifies some of the major causes of and motivations for political memoir writing in Australia, adopting the Rudd-Gillard Labor cabinet as a collective case study. Using a combination of empirical, literary and oral research methodologies, I argue that political memoirs are manifestations of political and historiographical purpose, written in response to and enabled by particular political and market environments. This case study explains the rapid proliferation of political memoirs at a particular moment in the mid-2010s, but also leads toward a more structural explanation as to why these books have been published prolifically in Australia since the mid-1990s. Politicians have considered themselves antagonised by hostile political and media narratives and, following internal and electoral defeat, have been presented with publishing opportunities with which to tell their side of the story or, as they see it, to “set the record straight.”

Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies

The recently reported “UK variant” (B.1.1.7) of SARS-CoV-2 is thought to be more infectious than previously circulating strains as a result of several changes, including the N501Y mutation. We present a 2.9-Å resolution cryo-electron microscopy (cryo-EM) structure of the complex between the ACE2 receptor and N501Y spike protein ectodomains that shows Y501 inserted into a cavity at the binding interface near Y41 of ACE2. This additional interaction provides a structural explanation for the increased ACE2 affinity of the N501Y mutant, and likely contributes to its increased infectivity. However, this mutation does not result in large structural changes, enabling important neutralization epitopes to be retained in the spike receptor binding domain. We confirmed this through biophysical assays and by determining cryo-EM structures of spike protein ectodomains bound to 2 representative potent neutralizing antibody fragments.

Structural basis of drug recognition by the multidrug transporter ABCG2

ABSTRACTABCG2 is an ATP-binding cassette (ABC) transporter whose function affects the pharmacokinetics of drugs and contributes to multidrug resistance of cancer cells. While its interaction with the endogenous substrate estrone-3-sulfate (E1S) has been elucidated at a structural level, the recognition and recruitment of exogenous compounds is not understood at sufficiently high resolution. Here we present three cryo-EM structures of nanodisc-reconstituted, human ABCG2 bound to anticancer drugs tariquidar, topotecan and mitoxantrone. To enable structural insight at high resolution, we used Fab fragments of the ABCG2-specific monoclonal antibody 5D3, which binds to the external side of the transporter but does not interfere with drug-induced stimulation of ATPase activity. We observed that the binding pocket of ABCG2 can accommodate a single tariquidar molecule in a C-shaped conformation, similar to one of the two tariquidar molecules bound to ABCB1, where tariquidar acts as an inhibitor. We also found single copies of topotecan and mitoxantrone bound between key phenylalanine residues. Mutagenesis experiments confirmed the functional importance of two residues in the binding pocket, F439 and N436. Using 3D variability analyses, we found a correlation between substrate binding and reduced dynamics of the nucleotide binding domains (NBDs), suggesting a structural explanation for drug-induced ATPase stimulation. Our findings provide insight into how ABCG2 differentiates between inhibitors and substrates and may guide a rational design of new modulators and substrates.