Variant-specific and reciprocal Hsp40 functions in Hsp104-mediated prion elimination.

The amyloid-based prions of Saccharomyces cerevisiae are heritable aggregates of misfolded proteins, passed to daughter cells following fragmentation by molecular chaperones including the J-protein Sis1, Hsp70 and Hsp104. Overexpression of Hsp104 efficiently cures cell populations of the prion [PSI+ ] by an alternative Sis1-dependent mechanism that is currently the subject of significant debate. Here, we broadly investigate the role of J-proteins in this process by determining the impact of amyloid polymorphisms (prion variants) on the ability of well-studied Sis1 constructs to compensate for Sis1 and ask whether any other S. cerevisiae cytosolic J-proteins are also required for this process. Our comprehensive screen, examining all 13 members of the yeast cytosolic/nuclear J-protein complement, uncovered significant variant-dependent genetic evidence for a role of Apj1 (antiprion DnaJ) in this process. For strong, but not weak [PSI+ ] variants, depletion of Apj1 inhibits Hsp104-mediated curing. Overexpression of either Apj1 or Sis1 enhances curing, while overexpression of Ydj1 completely blocks it. We also demonstrated that Sis1 was the only J-protein necessary for the propagation of at least two weak [PSI+ ] variants and no J-protein alteration, or even combination of alterations, affected the curing of weak [PSI+ ] variants, suggesting the possibility of biochemically distinct, variant-specific Hsp104-mediated curing mechanisms.

Functional diversification of hsp40: distinct j-protein functional requirements for two prions allow for chaperone-dependent prion selection.

Yeast prions are heritable amyloid aggregates of functional yeast proteins; their propagation to subsequent cell generations is dependent upon fragmentation of prion protein aggregates by molecular chaperone proteins. Mounting evidence indicates the J-protein Sis1 may act as an amyloid specificity factor, recognizing prion and other amyloid aggregates and enabling Ssa and Hsp104 to act in prion fragmentation. Chaperone interactions with prions, however, can be affected by variations in amyloid-core structure resulting in distinct prion variants or 'strains'. Our genetic analysis revealed that Sis1 domain requirements by distinct variants of [PSI+] are strongly dependent upon overall variant stability. Notably, multiple strong [PSI+] variants can be maintained by a minimal construct of Sis1 consisting of only the J-domain and glycine/phenylalanine-rich (G/F) region that was previously shown to be sufficient for cell viability and [RNQ+] prion propagation. In contrast, weak [PSI+] variants are lost under the same conditions but maintained by the expression of an Sis1 construct that lacks only the G/F region and cannot support [RNQ+] propagation, revealing mutually exclusive requirements for Sis1 function between these two prions. Prion loss is not due to [PSI+]-dependent toxicity or dependent upon a particular yeast genetic background. These observations necessitate that Sis1 must have at least two distinct functional roles that individual prions differentially require for propagation and which are localized to the glycine-rich domains of the Sis1. Based on these distinctions, Sis1 plasmid-shuffling in a [PSI+]/[RNQ+] strain permitted J-protein-dependent prion selection for either prion. We also found that, despite an initial report to the contrary, the human homolog of Sis1, Hdj1, is capable of [PSI+] prion propagation in place of Sis1. This conservation of function is also prion-variant dependent, indicating that only one of the two Sis1-prion functions may have been maintained in eukaryotic chaperone evolution.

Improving guideline-based anticoagulation in atrial fibrillation: A systematic literature review of prospective trials.

BACKGROUND: Guidelines for anticoagulation in patients with atrial fibrillation (AF) aim to decrease the risk of ischemic stroke. However, there is a gap in actual practice between patients who have an indication for anticoagulation and those who are actually prescribed anticoagulation. OBJECTIVE: We sought to evaluate the efficacy of prior population-based interventions aimed at decreasing this AF anticoagulation gap. METHODS: This study was prospectively registered in the International Prospective Register of Systematic Reviews database (CRD42021287875). A systematic literature review was conducted to obtain all prospective individually randomized and cluster randomized trials by searching 4 electronic databases: PubMed, Google Scholar, Web of Science, and Medline. RESULTS: After a review of 1474 studies, 20 trials were included in this systematic literature review. Forty-five percent were effective in decreasing the AF anticoagulation gap. Trial interventions that improved anticoagulation prescribing included 6 trials of electronic risk assessment or decision support, 1 trial of provider education, 2 trials of new protocol or pathway, and 2 trials of patient education. Six of 15 ambulatory trials, 2 of 4 inpatient trials, and 1 trial that spanned inpatient and outpatient settings improved anticoagulation prescribing rates. Interventions focused on patient education, provider education, and electronic risk assessment or decision support increased absolute appropriate anticoagulation prescribing by 8.3%, 4.9%, and 2.0%, respectively. CONCLUSION: Interventions aimed at improving anticoagulation prescribing patterns in AF can be effective, although there is heterogeneity in outcomes across intervention type. The most effective interventions appeared to target patient education, provider education, and electronic risk assessment or decision support.

Natural Language Processing for the Ascertainment and Phenotyping of Left Ventricular Hypertrophy and Hypertrophic Cardiomyopathy on Echocardiogram Reports.

Extracting and accurately phenotyping electronic health documentation is critical for medical research and clinical care. We sought to develop a highly accurate and open-source natural language processing (NLP) module to ascertain and phenotype left ventricular hypertrophy (LVH) and hypertrophic cardiomyopathy (HCM) diagnoses from echocardiogram reports within a diverse hospital network. After the initial development on 17,250 echocardiogram reports, 700 unique reports from 6 hospitals were randomly selected from data repositories within the Mass General Brigham healthcare system and manually adjudicated by physicians for 10 subtypes of LVH and diagnoses of HCM. Using an open-source NLP system, the module was formally tested on 300 training set reports and validated on 400 reports. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated to assess the discriminative accuracy of the NLP module. The NLP demonstrated robust performance across the 10 LVH subtypes, with the overall sensitivity and specificity exceeding 96%. In addition, the NLP module demonstrated excellent performance in detecting HCM diagnoses, with sensitivity and specificity exceeding 93%. In conclusion, we designed a highly accurate NLP module to determine the presence of LVH and HCM on echocardiogram reports. Our work demonstrates the feasibility and accuracy of NLP to detect diagnoses on imaging reports, even when described in free text. This module has been placed in the public domain to advance research, trial recruitment, and population health management for patients with LVH-associated conditions.

Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP)-the age-related clonal expansion of blood stem cells with leukemia-associated mutations-is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear. OBJECTIVES: This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD. METHODS: Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression. RESULTS: Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001). CONCLUSIONS: CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.

Severe babesiosis with associated splenic infarcts and asplenia.

We describe two patients who presented with severe autoimmune hemolytic anemia in the setting of babesiosis. Notably, one patient was immunocompetent but was found to have splenic infarcts of uncertain duration, while the other patient developed disease in the context of asplenia secondary to prior surgical removal of the spleen. Both patients received antibiotics and transfusion support and eventually made a full recovery. While the patient in case 1 had parasitemia >10%, neither patient ultimately required therapeutic red blood cell exchange transfusion during the course of their respective hospitalizations. Our two cases emphasize the importance of recognizing the hemolytic anemia component of this potentially life-threatening infection, and the importance of rapidly initiating treatment in these complex clinical situations.

ACC/AHA Versus ESC Guidelines on Prosthetic Heart Valve Management: JACC Guideline Comparison.

Prosthetic heart valve interventions continue to evolve with new innovations in surgical and transcatheter technologies. We compared the recommendations from the 2017 American College of Cardiology/American Heart Association guidelines for management of patients with prosthetic heart valves with the 2017 European Society of Cardiology guidelines. The 2 documents differed regarding recommendations for follow-up imaging, the choice of biological versus mechanical prosthesis, bridging therapies, role of aspirin, use of fibrinolytic therapy for prosthetic valve thrombosis, and management of paravalvular regurgitation. This review highlights the differences between the 2 guidelines, summarizes new evidence, and offers recommendations for the management of patients with prosthetic heart valves in these areas of controversy.

Hsp40 function in yeast prion propagation: Amyloid diversity necessitates chaperone functional complexity.

Yeast prions are heritable protein-based elements, most of which are formed of amyloid aggregates that rely on the action of molecular chaperones for transmission to progeny. Prions can form distinct amyloid structures, known as 'strains' in mammalian systems, that dictate both pathological progression and cross-species infection barriers. In yeast these same amyloid structural polymorphisms, called 'variants', dictate the intensity of prion-associated phenotypes and stability in mitosis. We recently reported that [PSI(+)] prion variants differ in the fundamental domain requirements for one chaperone, the Hsp40/J-protein Sis1, which are mutually exclusive between 2 different yeast prions, demonstrating a functional plurality for Sis1. Here we extend that analysis to incorporate additional data that collectively support the hypothesis that Sis1 has multiple functional roles that can be accomplished by distinct sets of domains. These functions are differentially required by distinct prions and prion variants. We also present new data regarding Hsp104-mediated prion elimination and show that some Sis1 functions, but not all, are conserved in the human homolog Hdj1/DNAJB1. Importantly, of the 10 amyloid-based prions indentified to date in Saccharomyces cerevisiae, the chaperone requirements of only 4 are known, leaving a great diversity of amyloid structures, and likely modes of amyloid-chaperone interaction, largely unexplored.