Where Are They Now(?): Two Decades of Longitudinal Outcome Assessment Data Linking Positive Student, Graduate Student, Career and Life Trajectory Decisions to Participation in Intercollegiate Competitive Debate

In 1997, Rogers (2002, 2007) launched an ambitious cohort-based study to specifically measure student outcomes from forensic participation with direct, empirical comparisons between a debate and non-debate group over an extended period through college, graduate school, professional careers, and life-trajectory decisions. This monograph offers a continuation of those earlier studies in order to provide almost two decades of empirical performance data and outcomes. In order for the reader to place the current study in context, it is helpful to review a brief update of the applicable literature and a brief explanation of the previous two studies before attempting to interpret new data

Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5′-untranslated region: Implications in Alzheimer’s disease

In addition to the devastating symptoms of dementia, Alzheimer’s disease (AD) is characterized by accumulation of the processing products of the amyloid-β (Aβ) peptide precursor protein (APP). APP’s non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3′-untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5′-UTR to upregulate APP translation and Aβ production. This upregulation is reduced but not eliminated by knockdown of argonaute 2. The target site for miR-346 overlaps with active sites for an iron-responsive element (IRE) and an interleukin-1 (IL-1) acute box element. IREs interact with iron response protein1 (IRP1), an iron-dependent translational repressor. In primary human brain cultures, miR-346 activity required chelation of Fe. In addition, miR-346 levels are altered in late-Braak stage AD. Thus, miR-346 plays a role in upregulation of APP in the CNS and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. Further work will be necessary to integrate other metals, and IL-1 into the Fe-miR-346 activity network. We, thus, propose a “FeAR” (Fe, APP, RNA) nexus in the APP 5′-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a “healthy FeAR” exists, activities of miR-346 and IRP/Fe interact to maintain APP homeostasis. Disruption of an element that targets the FeAR nexus would lead to pathogenic disruption of APP translation and protein production

The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen

Increased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5'untranslated region (5'UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5'UTR, whereas, by contrast, the H-ferritin 5'UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5'UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5'UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1 μM IC(50)) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo

The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5′Untranslated-Region-Directed Translation Blockers of the Parkinson's Alpha Synuclein Expression

There is compelling support for limiting expression of alpha-synuclein (α-syn) in the brains of Parkinson's disease (PD) patients. An increase of SNCA gene copy number can genetically cause familial PD where increased dose of this pathogenic protein correlates with severity of symptoms (triplication of the SNCA gene causes dementia in PD patients). Gene promoter polymorphisms were shown to increase α-synuclein expression as a risk for PD. Cholinesterase inhibitors can clinically slow cognitive decline in the later stages of PD etiology similar to their widespread use in Alzheimer's disease (AD). Pertinent to this, we identified that the well-tolerated anticholinesterase, phenserine, blocked neural SNCA mRNA translation and tested for targeting via its 5′untranslated region (5′UTR) in a manner similar to its action to limit the expression of the AD-specific amyloid precursor protein (APP). Posiphen, its better-tolerated (+) enantiomer (devoid of anticholinesterase action), repressed neural α-synuclein translation. Primary metabolic analogs of posiphen were, likewise, characterized using primary fetal neurons grown ex vivo from the brains of Parkinson's transgenic mice expressing the human SNCA gene

Comparison of Outcomes in Level I vs Level II Trauma Centers in Patients Undergoing Craniotomy or Craniectomy for Severe Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) carries a devastatingly high rate of morbidity and mortality. OBJECTIVE: To assess whether patients undergoing craniotomy/craniectomy for severe TBI fare better at level I than level II trauma centers in a mature trauma system. METHODS: The data were extracted from the Pennsylvania Trauma Outcome Study database. Inclusion criteria were patients \u3e 18 yr with severe TBI (Glasgow Coma Scale [GCS] score less than 9) undergoing craniotomy or craniectomy in the state of Pennsylvania from January 1, 2002 through September 30, 2017. RESULTS: Of 3980 patients, 2568 (64.5%) were treated at level I trauma centers and 1412 (35.5%) at level II centers. Baseline characteristics were similar between the 2 groups except for significantly worse GCS scores at admission in level I centers (P = .002). The rate of in-hospital mortality was 37.6% in level I centers vs 40.4% in level II centers (P = .08). Mean Functional Independence Measure (FIM) scores at discharge were significantly higher in level I (10.9 ± 5.5) than level II centers (9.8 ± 5.3; P \u3c .005). In multivariate analysis, treatment at level II trauma centers was significantly associated with in-hospital mortality (odds ratio, 1.2; 95% confidence interval, 1.03-1.37; P = .01) and worse FIM scores (odds ratio, 1.4; 95% confidence interval, 1.1-1.7; P = .001). Mean hospital and ICU length of stay were significantly longer in level I centers (P \u3c .005). CONCLUSION: This study showed superior functional outcomes and lower mortality rates in patients undergoing a neurosurgical procedure for severe TBI in level I trauma centers

Revised Masses and Densities of the Planets around Kepler-10

Determining which small exoplanets have stony-iron compositions is necessary for quantifying the occurrence of such planets and for understanding the physics of planet formation. Kepler-10 hosts the stony-iron world Kepler-10b, and also contains what has been reported to be the largest solid silicate-ice planet, Kepler-10c. Using 220 radial velocities (RVs), including 72 precise RVs from Keck-HIRES of which 20 are new from 2014 to 2015, and 17 quarters of Kepler photometry, we obtain the most complete picture of the Kepler-10 system to date. We find that Kepler-10b (R_p = 1.47 R_⊕) has mass 3.72 ± 0.42 M_⊕ and density 6.46 ± 0.73 g cm^(-3). Modeling the interior of Kepler-10b as an iron core overlaid with a silicate mantle, we find that the iron core constitutes 0.17 ± 0.11 of the planet mass. For Kepler-10c (R_p = 2.35 R_⊕) we measure mass 13.98 ± 1.79 M_⊕ and density 5.94 ± 0.76 g cm^(-3), significantly lower than the mass computed in Dumusque et al. (17.2 ± 1.9 M_⊕). Our mass measurement of Kepler-10c rules out a pure stony-iron composition. Internal compositional modeling reveals that at least 10% of the radius of Kepler-10c is a volatile envelope composed of hydrogen–helium (0.2% of the mass, 16% of the radius) or super-ionic water (28% of the mass, 29% of the radius). However, we note that analysis of only HIRES data yields a higher mass for planet b and a lower mass for planet c than does analysis of the HARPS-N data alone, with the mass estimates for Kepler-10 c being formally inconsistent at the 3σ level. Moreover, dividing the data for each instrument into two parts also leads to somewhat inconsistent measurements for the mass of planet c derived from each observatory. Together, this suggests that time-correlated noise is present and that the uncertainties in the masses of the planets (especially planet c) likely exceed our formal estimates. Transit timing variations (TTVs) of Kepler-10c indicate the likely presence of a third planet in the system, KOI-72.X. The TTVs and RVs are consistent with KOI-72.X having an orbital period of 24, 71, or 101 days, and a mass from 1 to 7 M_⊕