The coronavirus disease 2019 pandemic has made deployment of an effective vaccine a global health priority. We evaluated the protective activity of a chimpanzee adenovirus-vectored vaccine encoding a ...prefusion stabilized spike protein (ChAd-SARS-CoV-2-S) in challenge studies with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mice expressing the human angiotensin-converting enzyme 2 receptor. Intramuscular dosing of ChAd-SARS-CoV-2-S induces robust systemic humoral and cell-mediated immune responses and protects against lung infection, inflammation, and pathology but does not confer sterilizing immunity, as evidenced by detection of viral RNA and induction of anti-nucleoprotein antibodies after SARS-CoV-2 challenge. In contrast, a single intranasal dose of ChAd-SARS-CoV-2-S induces high levels of neutralizing antibodies, promotes systemic and mucosal immunoglobulin A (IgA) and T cell responses, and almost entirely prevents SARS-CoV-2 infection in both the upper and lower respiratory tracts. Intranasal administration of ChAd-SARS-CoV-2-S is a candidate for preventing SARS-CoV-2 infection and transmission and curtailing pandemic spread.
Display omitted
•Chimpanzee adenoviral vaccines encoding stabilized S induce neutralizing Abs•Chimpanzee adenoviral vaccines protect against SARS-CoV-2 infection and pneumonia•Intranasal vaccine delivery generates robust mucosal B and T cell responses•Intranasal ChAd-SARS-CoV-2 prevents upper and lower respiratory tract infection
Intranasal or intramuscular immunization of ChAd-SARS-CoV-2, a chimpanzee adenoviral vaccine encoding stabilized spike protein, prevents SARS-CoV-2 lung infection and pneumonia in mice. In particular, intranasally delivered ChAd-SARS-CoV-2 uniquely prevents both upper and lower respiratory tract infections, potentially protecting against SARS-CoV-2 infection and transmission.
Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97-98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic ...landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Parkinson's disease is a synucleinopathy that is characterized by motor dysfunction, death of midbrain dopaminergic neurons and accumulation of α-synuclein (α-Syn) aggregates. Evidence suggests that ...α-Syn aggregation can originate in peripheral tissues and progress to the brain via autonomic fibers. We tested this by inoculating the duodenal wall of mice with α-Syn preformed fibrils. Following inoculation, we observed gastrointestinal deficits and physiological changes to the enteric nervous system. Using the AAV-PHP.S capsid to target the lysosomal enzyme glucocerebrosidase for peripheral gene transfer, we found that α-Syn pathology is reduced due to the increased expression of this protein. Lastly, inoculation of α-Syn fibrils in aged mice, but not younger mice, resulted in progression of α-Syn histopathology to the midbrain and subsequent motor defects. Our results characterize peripheral synucleinopathy in prodromal Parkinson's disease and explore cellular mechanisms for the gut-to-brain progression of α-Syn pathology.
The drop box location problem Schmidt, Adam; Albert, Laura A.
IISE transactions,
04/2024, Letnik:
ahead-of-print, Številka:
ahead-of-print
Journal Article
Recenzirano
For decades, voting-by-mail and the use of ballot drop boxes has substantially grown within the USA, and in response, many USA election officials have added drop boxes to their voting infrastructure. ...However, existing guidance for locating drop boxes is limited. In this article, we introduce an integer programming model, the Drop Box Location Problem (DBLP), to locate drop boxes. The DBLP considers criteria of cost, voter access, and risk. The cost of the drop box system is determined by the fixed cost of adding drop boxes and the operational cost of a collection tour by a bipartisan team who regularly collects ballots from selected locations. The DBLP utilizes covering sets to ensure each voter is in close proximity to a drop box and incorporates a novel measure of access to measure the ability to use multiple voting pathways to vote. The DBLP is shown to be NP-hard, and we introduce a heuristic to generate a large number of feasible solutions for policy makers to select from a posteriori. Using a real-world case study of Milwaukee, WI, U.S., we study the benefits of the DBLP. The results demonstrate that the proposed optimization model identifies drop box locations that perform well across multiple criteria. The results also demonstrate that the trade-off between cost, access, and risk is non-trivial, which supports the use of the proposed optimization-based approach to select drop box locations.
IMPORTANCE: Little is known regarding the association between level of blood pressure (BP) in young adulthood and cardiovascular disease (CVD) events by middle age. OBJECTIVE: To assess whether young ...adults who developed hypertension, defined by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) BP guideline, before age 40 years have higher risk for CVD events compared with those who maintained normal BP. DESIGN, SETTING, AND PARTICIPANTS: Analyses were conducted in the prospective cohort Coronary Artery Risk Development in Young Adults (CARDIA) study, started in March 1985. CARDIA enrolled 5115 African American and white participants aged 18 to 30 years from 4 US field centers (Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California). Outcomes were available through August 2015. EXPOSURES: Using the highest BP measured from the first examination to the examination closest to, but not after, age 40 years, each participant was categorized as having normal BP (untreated systolic BP SBP <120 mm Hg and diastolic BP DBP <80 mm Hg; n = 2574); elevated BP (untreated SBP 120-129 mm Hg and DBP <80 mm Hg; n = 445); stage 1 hypertension (untreated SBP 130-139 mm Hg or DBP 80-89 mm Hg; n = 1194); or stage 2 hypertension (SBP ≥140 mm Hg, DBP ≥90 mm Hg, or taking antihypertensive medication; n = 638). MAIN OUTCOMES AND MEASURES: CVD events: fatal and nonfatal coronary heart disease (CHD), heart failure, stroke, transient ischemic attack, or intervention for peripheral artery disease (PAD). RESULTS: The final cohort included 4851 adults (mean age when follow-up for outcomes began, 35.7 years SD, 3.6; 2657 women 55%; 2441 African American 50%; 206 taking antihypertensive medication 4%). Over a median follow-up of 18.8 years, 228 incident CVD events occurred (CHD, 109; stroke, 63; heart failure, 48; PAD, 8). CVD incidence rates for normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension were 1.37 (95% CI, 1.07-1.75), 2.74 (95% CI, 1.78-4.20), 3.15 (95% CI, 2.47-4.02), and 8.04 (95% CI, 6.45-10.03) per 1000 person-years, respectively. After multivariable adjustment, hazard ratios for CVD events for elevated BP, stage 1 hypertension, and stage 2 hypertension vs normal BP were 1.67 (95% CI, 1.01-2.77), 1.75 (95% CI, 1.22-2.53), and 3.49 (95% CI, 2.42-5.05), respectively. CONCLUSIONS AND RELEVANCE: Among young adults, those with elevated blood pressure, stage 1 hypertension, and stage 2 hypertension before age 40 years, as defined by the blood pressure classification in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, had significantly higher risk for subsequent cardiovascular disease events compared with those with normal blood pressure before age 40 years. The ACC/AHA blood pressure classification system may help identify young adults at higher risk for cardiovascular disease events.
•Information and communication technology supply chains present risks that are complex and difficult to manage.•We present new optimization models to support supply chain risk ...management.•Optimization models with two risk reduction objectives select a portfolio of security controls subject to a budget constraint.•The stochastic model informs security investment decisions under uncertainty.•The computational results highlight how to construct a portfolio of security controls that is effective across multiple criteria.
Information and communication technology supply chains present risks that are complex and difficult for organizations to manage. The cost and benefit of proposed security controls must be assessed to best match an organizational risk tolerance and direct the use of security resources. In this paper, we present integer and stochastic optimization models for selecting a portfolio of security controls within an organizational budget. We consider two objectives: to maximize the risk reduction across all potential attacks and to maximize the number of attacks whose risk levels are lower than a risk threshold after security controls are applied. Deterministic and stochastic bi-objective budgeted difficulty-threshold control selection problems are formulated for selecting mitigating controls to reflect an organization’s risk preference. In the stochastic problem, we consider uncertainty as to whether the selected controls can reduce the risks associated with attacks. We demonstrate through a computational study that the trade-off between the two objectives is important to consider for certain risk preferences and budgets. We demonstrate the value of the stochastic model when a relatively high number of attacks are desired to be secured past a risk threshold and show the deterministic solution provides near optimal solutions otherwise. We provide an analysis of model solutions.
IMPORTANCE: The public health implications of e-cigarettes depend, in part, on whether e-cigarette use affects the risk of cigarette smoking. OBJECTIVE: To perform a systematic review and ...meta-analysis of longitudinal studies that assessed initial use of e-cigarettes and subsequent cigarette smoking. DATA SOURCES: PubMed, EMBASE, Cochrane Library, Web of Science, the 2016 Society for Research on Nicotine and Tobacco 22nd Annual Meeting abstracts, the 2016 Society of Behavioral Medicine 37th Annual Meeting & Scientific Sessions abstracts, and the 2016 National Institutes of Health Tobacco Regulatory Science Program Conference were searched between February 7 and February 17, 2017. The search included indexed terms and text words to capture concepts associated with e-cigarettes and traditional cigarettes in articles published from database inception to the date of the search. STUDY SELECTION: Longitudinal studies reporting odds ratios for cigarette smoking initiation associated with ever use of e-cigarettes or past 30-day cigarette smoking associated with past 30-day e-cigarette use. Searches yielded 6959 unique studies, of which 9 met inclusion criteria (comprising 17 389 adolescents and young adults). DATA EXTRACTION AND SYNTHESIS: Study quality and risk of bias were assessed using the Newcastle-Ottawa Scale and the Risk of Bias in Non-randomized Studies of Interventions tool, respectively. Data and estimates were pooled using random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: Among baseline never cigarette smokers, cigarette smoking initiation between baseline and follow-up. Among baseline non–past 30-day cigarette smokers who were past 30-day e-cigarette users, past 30-day cigarette smoking at follow-up. RESULTS: Among 17 389 adolescents and young adults, the ages ranged between 14 and 30 years at baseline, and 56.0% were female. The pooled probabilities of cigarette smoking initiation were 30.4% for baseline ever e-cigarette users and 7.9% for baseline never e-cigarette users. The pooled probabilities of past 30-day cigarette smoking at follow-up were 21.5% for baseline past 30-day e-cigarette users and 4.6% for baseline non–past 30-day e-cigarette users. Adjusting for known demographic, psychosocial, and behavioral risk factors for cigarette smoking, the pooled odds ratio for subsequent cigarette smoking initiation was 3.62 (95% CI, 2.42-5.41) for ever vs never e-cigarette users, and the pooled odds ratio for past 30-day cigarette smoking at follow-up was 4.28 (95% CI, 2.52-7.27) for past 30-day e-cigarette vs non–past 30-day e-cigarette users at baseline. A moderate level of heterogeneity was observed among studies (I2 = 60.1%). CONCLUSIONS AND RELEVANCE: e-Cigarette use was associated with greater risk for subsequent cigarette smoking initiation and past 30-day cigarette smoking. Strong e-cigarette regulation could potentially curb use among youth and possibly limit the future population-level burden of cigarette smoking.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 ...infection, we identify human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of angiotensin-converting enzyme 2 (ACE2) expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious. Anti-S monoclonal antibodies differentially neutralize SARS-CoV-2 E484D S in H522 cells as compared to ACE2-expressing cells. Sera from vaccinated individuals block this alternative entry mechanism, whereas convalescent sera are less effective. Although the H522 receptor remains unknown, depletion of surface heparan sulfates block H522 infection. Temporally resolved transcriptomic and proteomic profiling reveal alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type I interferon signaling. These findings establish an alternative SARS-CoV-2 host cell receptor for the E484D SARS-CoV-2 variant, which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.
Display omitted
•H522 human lung cells support SARS-CoV-2 replication independent of ACE2•Viral entry in H522 cells requires the E484D mutation in spike•H522 infection requires surface heparan sulfates and clathrin-mediated endocytosis•Sera from vaccinated patients block the alternative entry pathway in H522 cells
Variants in the SARS-CoV-2 spike enhance transmissibility and disease severity. Puray-Chavez et al. report a human lung cell line that naturally supports E484 variant SARS-CoV-2 infection independently of ACE2 expression. This alternative entry mechanism may underlie the complex COVID-19 pathogenesis and impact future therapeutic design.
Obesity is a common disease and a known risk factor for many other conditions such as hypertension, type 2 diabetes, and cancer. Treatment options for obesity include lifestyle changes, ...pharmacotherapy, and surgical interventions such as bariatric surgery. In this study, we examine the use of prescription drugs and dietary supplements by the individuals with obesity.
We conducted a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) data 2003-2018. We used multivariate logistic regression to analyze the correlations of demographics and obesity status with the use of prescription drugs and dietary supplement use. We also built machine learning models to classify prescription drug and dietary supplement use using demographic data and obesity status.
Individuals with obesity are more likely to take cardiovascular agents (OR = 2.095, 95% CI 1.989-2.207) and metabolic agents (OR = 1.658, 95% CI 1.573-1.748) than individuals without obesity. Gender, age, race, poverty income ratio, and insurance status are significantly correlated with dietary supplement use. The best performing model for classifying prescription drug use had the accuracy of 74.3% and the AUROC of 0.82. The best performing model for classifying dietary supplement use had the accuracy of 65.3% and the AUROC of 0.71.
This study can inform clinical practice and patient education of the use of prescription drugs and dietary supplements and their correlation with obesity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
10.
Editorial 2024 Eyre-Walker, Adam; Katz, Laura A
Genome biology and evolution,
02/2024, Letnik:
16, Številka:
2
Journal Article
PDF
