13 research outputs found
Will Aging Baby Boomers Bust the Federal Budget?
The authors analyze in three steps the influence of the projected mortality decline on the long-run finances of the Social Security System. First, mortality decline adds person years of life which are distributed across the life cycle. The interaction of this distribution with the age distribution of taxes minus benefits determines the steady state financial consequences of mortality decline. Second, examination of past mortality trends in the United State and of international trends in low mortality populations, suggests that mortality will decline much faster than foreseen by the SSA\u27s forecasts. Third, based on work on stochastic demographic forecasting, stochastic forecasts of the system\u27s actuarial balance are derived, indicating a broader range of demographic uncertainty than in the latest SSA forecasts, and a relatively greater contribution to uncertainty from fertility than mortality
Structurally Programmed Assembly of Translation Initiation Nanoplex for Superior mRNA Delivery
Messenger
RNA (mRNA) represents a promising class of nucleic-acid-based
therapeutics. While numerous nanocarriers have been developed for
mRNA delivery, the inherent labile nature of mRNA results in a very
low transfection efficiency and poor expression of desired protein.
Here we preassemble the mRNA translation initiation structure through
an inherent molecular recognition between 7-methylguanosine (m<sup>7</sup>G)-capped mRNA and eukaryotic initiation factor 4E (eIF4E)
protein to form ribonucleoproteins (RNPs), thereby mimicking the first
step of protein synthesis inside cells. Subsequent electrostatic stabilization
of RNPs with structurally tunable cationic carriers leads to nanosized
complexes (nanoplexes), which elicit high levels of mRNA transfection
in different cell types by enhancing intracellular mRNA stability
and protein synthesis. By investigating a family of synthetic polypeptides
bearing different side group arrangements of cationic charge, we find
that the molecular structure modulates the nanoscale distance between
the mRNA strand and the eIF4E protein inside the nanoplex, which directly
impacts the enhancement of mRNA transfection. To demonstrate the biomedical
potential of this approach, we use this approach to introduce mRNA/eIF4E
nanoplexes to murine dendritic cells, resulting in increased activation
of cytotoxic CD8 T cells <i>ex vivo</i>. More importantly,
eIF4E enhances gene expression in lungs following a systemic delivery
of luciferase mRNA/eIF4E in mice. Collectively, this bioinspired molecular
assembly method could lead to a new paradigm of gene delivery
Enhancing humoral immunity via sustained-release implantable microneedle patch vaccination
Sustained exposure of lymphoid tissues to vaccine antigens promotes humoral immunity, but traditional bolus immunizations lead to rapid antigen clearance. We describe a technology to tailor vaccine kinetics in a needle-free platform translatable to human immunization. Solid pyramidal microneedle (MN) arrays were fabricated with silk fibroin protein tips encapsulating a stabilized HIV envelope trimer immunogen and adjuvant, supported on a dissolving polymer base. Upon brief skin application, vaccine-loaded silk tips are implanted in the epidermis/upper dermis where they release vaccine over a time period determined by the crystallinity of the silk matrix. Following MN immunization in mice, Env trimer was released over 2 wk in the skin, correlating with increased germinal center (GC) B cell responses, a ∼1,300-fold increase in serum IgG titers and a 16-fold increase in bone marrow (BM) plasma cells compared with bolus immunization. Thus, implantable MNs provide a practical means to substantially enhance humoral immunity to subunit vaccines.National Institute of Allergy and Infectious Diseases (Awards UM1AI100663 and AI104715)National Cancer Institute (Grant P30-CA14051
Prognostic value of dehydroepiandrosterone-sulfate and other parameters of adrenal function in acute ischemic stroke
BACKGROUND AND PURPOSE: Acute stroke has a high morbidity and mortality. We evaluated the predictive value of adrenal function testing in acute ischemic stroke. METHODS: In a cohort of 231 acute ischemic stroke patients, we measured dehydroepiandrosterone (DHEA), DHEA-Sulfate (DHEAS), cortisol at baseline and 30 minutes after stimulation with 1 ug ACTH. Delta cortisol, the amount of rise in the 1 ug ACTH-test, was calculated. Primary endpoint was poor functional outcome defined as modified Rankin scale 3-6 after 1 year. Secondary endpoint was nonsurvival after 1 year. RESULTS: Logistic regression analysis showed that DHEAS (OR 1.21, 95% CI 1.01-1.49), but not DHEA (OR 1.01, 95% CI 0.99-1.04), was predictive for adverse functional outcome. Neither DHEA (OR 0.99, 95% CI 0.96-1.03) nor DHEAS (OR 1.10, 95% CI 0.82-1.44) were associated with mortality. Baseline and stimulated cortisol were predictive for mortality (OR 1.41, 95% CI 1.20-1.71; 1.35, 95% CI 1.15-1.60), but only basal cortisol for functional outcome (OR 1.20, 95% CI 1.04-1.38). Delta cortisol was not predictive for functional outcome (OR 0.86, 95% CI 0.71-1.05) or mortality (OR 0.92, 95% CI 0.72-1.17). The ratios cortisol/DHEA and cortisol/DHEAS discriminated between favorable outcome and nonsurvival (both p<0.0001) and between unfavorable outcome and nonsurvival (p = 0.0071 and 0.0029), but are not independent predictors for functional outcome or mortality in multivariate analysis (adjusted OR for functional outcome for both 1.0 (95% CI 0.99-1.0), adjusted OR for mortality for both 1.0 (95% CI 0.99-1.0 and 1.0-1.01, respectively)). CONCLUSION: DHEAS and the cortisol/DHEAS ratio predicts functional outcome 1 year after stroke whereas cortisol levels predict functional outcome and mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT00390962 (Retrospective analysis of this cohort)