997 research outputs found

    APP processing is regulated by cytoplasmic phosphorylation

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    Amyloid-β peptide (Aβ) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the β-secretase, BACE1. Western blot analysis reveals increased levels of T668-phosphorylated APP COOH-terminal fragments in hippocampal lysates from many AD but not control subjects. Importantly, P-APP cofractionates with endosome markers and BACE1 in an iodixanol gradient and displays extensive colocalization with BACE1 in rat primary cortical neurons. Furthermore, APP COOH-terminal fragments generated by BACE1 are preferentially phosphorylated on T668 verses those produced by α-secretase. The production of Aβ is significantly reduced when phosphorylation of T668 is either abolished by mutation or inhibited by T668 kinase inhibitors. Together, these results suggest that T668 phosphorylation may facilitate the BACE1 cleavage of APP to increase Aβ generation

    Effects of coronavirus disease pandemic on tuberculosis notifications, Malawi

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    The coronavirus disease (COVID-19) pandemic might affect tuberculosis (TB) diagnosis and patient care. We analyzed a citywide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi did not have an official COVID-19 lockdown but closed schools and borders on March 23, 2020. In an interrupted time series analysis, we noted an immediate 35.9% reduction in TB notifications in April 2020; notifications recovered to near prepandemic numbers by December 2020. However, 333 fewer cumulative TB notifications were received than anticipated. Women and girls were affected more (30.7% fewer cases) than men and boys (20.9% fewer cases). Fear of COVID-19 infection, temporary facility closures, inadequate personal protective equipment, and COVID-19 stigma because of similar symptoms to TB were mentioned as reasons for fewer people being diagnosed with TB. Public health measures could benefit control of both TB and COVID-19, but only if TB diagnostic services remain accessible and are considered safe to attend.Peer reviewe

    Engagement in the Data Collection Phase of the Scientific Process is Key for Enhancing Learning Gains

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    Most programs that create opportunities for the public to engage in scientific research invite the public to collect data, but there is a call to expand opportunities for engagement in additional aspects of the scientific process. One reason behind this call is the hypothesis that people who participate to a greater degree in the scientific process experience more robust learning outcomes. To test this hypothesis, we conducted a quasi-experiment by using a pre-post survey design and comparing varying degrees of participation in a Bird Cams Lab investigation. Bird Cams Lab was a virtual space in which the public worked with scientists to design and implement co-created investigations involving live streaming or recorded footage of birds. We found that the higher the degree of participation in the investigation, the greater the increase in content knowledge, self-efficacy, and self-reported improvement in science inquiry skills. Interestingly, involvement in data collection was associated with the greatest gains in content knowledge and self-efficacy regardless of involvement in other parts of the scientific process. For programs with limited funding and resources that seek to increase participants’ content knowledge and self-efficacy, focusing efforts on supporting data collection may be the most impactful

    Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.

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    Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers

    Impact of COVID-19 on tuberculosis notifications in Blantyre Malawi: an interrupted time series analysis and qualitative study with healthcare workers.

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    COVID-19 may impact on tuberculosis (TB) diagnosis and care. We analysed a city-wide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi had no official “lockdown” but closed schools and borders on 23 March 2020. In interrupted time series analysis, there was an immediate 35.9% reduction in TB notifications (95% CI 22.0 to 47.3%) in April, which recovered to near pre-pandemic numbers by December 2020, but with 333 (95% CI 291 to 375) fewer cumulative notifications than anticipated. Women and girls were impacted (30.7% fewer cases, 95% CI 28.4 to 33.0%) more than men and boys (20.9% fewer, 95% CI 18.5 to 23.3). Fear of COVID-19 infection, temporary facility closure, inadequate protective equipment and COVID-19 stigma with similar presenting symptoms to TB were mentioned. Public health measures could benefit both TB and COVID-19, but only if diagnostic services remain accessible and are considered safe to attend

    A Screen for Spore Wall Permeability Mutants Identifies a Secreted Protease Required for Proper Spore Wall Assembly

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    The ascospores of Saccharomyces cerevisiae are surrounded by a complex wall that protects the spores from environmental stresses. The outermost layer of the spore wall is composed of a polymer that contains the cross-linked amino acid dityrosine. This dityrosine layer is important for stress resistance of the spore. This work reports that the dityrosine layer acts as a barrier blocking the diffusion of soluble proteins out of the spore wall into the cytoplasm of the ascus. Diffusion of a fluorescent protein out of the spore wall was used as an assay to screen for mutants affecting spore wall permeability. One of the genes identified in this screen, OSW3 (RRT12/YCR045c), encodes a subtilisin-family protease localized to the spore wall. Mutation of the active site serine of Osw3 results in spores with permeable walls, indicating that the catalytic activity of Osw3 is necessary for proper construction of the dityrosine layer. These results indicate that dityrosine promotes stress resistance by acting as a protective shell around the spore. OSW3 and other OSW genes identified in this screen are strong candidates to encode enzymes involved in assembly of this protective dityrosine coat

    Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection

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    IMPORTANCE: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. OBJECTIVE: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. EXPOSURE: SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES: PASC and 44 participant-reported symptoms (with severity thresholds). RESULTS: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. CONCLUSIONS AND RELEVANCE: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC

    A communal catalogue reveals Earth’s multiscale microbial diversity

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    Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity
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