The effect of traumatic brain injury on tau pathology by a potential seeding mechanism

The misfolding, aggregation and accumulation of specific proteins is the overarching concept in protein misfolding disorders (PMDs). The microtubule associated protein tau is known to form insoluble filaments known as neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (pTau) found in a subset of PMDs called tauopathies, such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE), among others. Misfolded tau engenders a structurally alternative intermediate conformation that is prone to aggregate having amyloidogenic properties. Formation of amyloids, such as tau aggregates, is proposed to follow a nucleation-polymerization model where misfolded, soluble oligomeric seeds can trigger native proteins to misfold and aggregate. The processes responsible for the initial formation of seeding competent protein aggregates is not known. One hypothesis is that an insult to the brain could be a trigger for developing aggregate pathology noted in PMDs. Traumatic Brain Injury (TBI) is a pervasive event with an estimated 10 million people worldwide being affected and is defined as an insult to the brain caused by an external force, which may result in impaired neuronal and/or physical functioning. Indeed, TBI is a strong risk factor for PMDs, and following TBI, there is a detection of pathological tau early in human cases. TBI may be a trigger for the formation of tau seeds that can spread pathology throughout the brain. Thus, our central hypothesis is that TBI induces the early formation of tau misfolded seeds as well as exacerbates tau pathology and spreading throughout the brain by a nucleation-polymerization process, which will then lead to pathological changes relative to disease. Our overarching goal of this work is to elucidate the effect of TBI on the induction, acceleration, and spreading of tau pathology and clinical signs. To assess this, we induced tau transgenic mice with moderate-severe TBI or repetitive mild TBI (rmTBI) and examined tau pathology and spreading. Moreover, the earliest detected tau seeds induced following rmTBI were tested for seeding capability by in vivo bioassay. This proposal provides novel molecular mechanisms for these deleterious diseases, such as AD and CTE, and their link to TBI

The Debate Confessional: Newt Gingrich, John King and Atoning for Past Sins

Religious affiliation has always played a prominent role in the vetting of US presidential candidates, especially for those seeking the nomination of the Republican Party. Candidates within that party must appeal to fiscal, foreign policy and social conservatives, the last of which contain significant numbers of self-described evangelical Christians. During the 2012 Republican Presidential Primary appeals to these social conservatives became as significant a factor as any other with a Mormon candidate, a Catholic candidate who made his faith a centerpiece of his campaign, and a divorced former Speaker who recently converted to Catholicism. With the race still very much in the air, this former Speaker, Newt Gingrich, came under fire for his prior marriage and just a few days before a pivotal primary in South Carolina his ex-wife taped an interview about his marriage to her which was set to air immediately after the last debate before the election in South Carolina. At the beginning of the debate the moderator, John King of CNN, provided Gingrich an opportunity to discuss the pending interview. His response changed the scope of that primary election, helping vault Gingrich to a significant victory in South Carolina with significant support from formerly hesitant social conservatives. In this essay we examine his response to King’s opening question at the debate through the lens of image restoration theory and argue Gingrich used specific strategies to appeal for support from the social conservatives in that state

Flight test pilot evaluation of a delayed flap approach procedure

Using NASA's CV-990 aircraft, a delayed flap approach procedure was demonstrated to nine guest pilots from the air transport industry. Four demonstration flights and 37 approaches were conducted under VFR weather conditions. A limited pilot evaluation of the delayed flap procedure was obtained from pilot comments and from questionaires they completed. Pilot acceptability, pilot workload, and ATC compatibility were quantitatively rated. The delayed flap procedure was shown to be feasible, and suggestions for further development work were obtained

Delayed flap approach procedures for noise abatement and fuel conservation

The NASA/Ames Research Center is currently investigating the delayed flap approach during which pilot actions are determined and prescribed by an onboard digital computer. The onboard digital computer determines the proper timing for the deployment of the landing gear and flaps based on the existing winds and airplane gross weight. Advisory commands are displayed to the pilot. The approach is flown along the conventional ILS glide slope but is initiated at a higher airspeed and in a clean aircraft configuration that allows for low thrust and results in reduced noise and fuel consumption. Topics discussed include operational procedures, pilot acceptability of these procedures, and fuel/noise benefits resulting from flight tests and simulation

Creating the Southern Region 4-H Volunteer Advisory Group

The SR4-HVAG combines the efforts of states to provide quality educational programming for volunteers and Extension professionals using an advisory group system. An advisory group rather than a council was created because the group provides programmatic input rather than sets policy. The purposes of the SR4-HVAG are to: provide a mechanism for volunteer input and perspective regarding educational, programmatic and developmental needs of volunteers and strengthen communication and delivery systems that provide for the continued sharing of resources and programmatic efforts in the Southern Region. Each state is represented by two volunteers and is facilitated by a state volunteerism specialist

Using an Innovative Multiple-Methods Approach to Evaluate Extension Conferences

Engaging attendees of a 4-H volunteer conference in a multiple-methods approach to conference evaluation met the needs of our conference planning team by resulting in diverse opportunities for determining impact, assessing satisfaction, and understanding conference participants\u27 experiences. The multiple-methods approach also appealed to conference participants by providing them with a variety of ways to share input and reflection while building a sense of community and belonging. Every participant was involved in multiple assessment strategies. We received both quantitative and qualitative data for assessing conference success and gathered impact data by using multiple creative evaluation tools

The Use of Focus Groups to Evaluate the Volunteer Conference of Southern States

Round table focus groups were used to evaluate the 2013 Volunteer Conference of Southern States. All 144 conference attendees were randomly assigned to one of 18 different round tables. A series of seven questions were discussed by the focus groups, which were moderated by a member of the Southern Region 4-H Volunteer Advisory Group. A recorder captured the discussion on a Mac Notebook. The responses from 18 networked were assimilated into a Word document, grouped by question. Qualitative data were analyzed by three raters as outlined by Culp & Pilat (1988). Input received was instrumental in planning the 2014 conference

THE MOLECULAR INTERACTION BETWEEN TYPE II DIABETES AND ALZHEIMER’S DISEASE THROUGH CROSS-SEEDING OF PROTEIN MISFOLDING

With the population of the world aging, the prominence of diseases such as Type II Diabetes (T2D) and Alzheimer’s disease (AD) are on the rise. In addition, patients with T2D have an increased risk of developing AD compared to age-matched individuals, and the number of AD patients with T2D is higher than among aged-matched non-AD patients. AD is a chronic and progressive dementia characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), neuronal loss, brain inflammation, and cognitive impairment. T2D involves the dysfunctional use of pancreatic insulin by the body resulting in insulin resistance, hyperglycemia, hyperinsulinemia, pancreatic beta cell (β-cell) death, and other complications. T2D and AD are considered protein misfolding disorders (PMDs). PMDs are characterized by the presence of misfolded protein aggregates, such as in T2D pancreas (islet amyloid polypeptide - IAPP) and in AD brain (amyloid– Aβ) of affected individuals. The misfolding and accumulation of these proteins follows a seeding-nucleation model where misfolded soluble oligomers act as nuclei to propagate misfolding by recruiting other native proteins. Cross-seeding occurs when oligomers composed by one protein seed the aggregation of a different protein. Our hypothesis is that the pathological interactions between T2D and AD may in part occur through cross-seeding of protein misfolding. To test this hypothesis, we examined how each respective aggregate (Aβ or IAPP) affects the disparate disease pathology through in vitro and in vivo studies. Assaying Aβ aggregates influence on T2D pathology, IAPP+/+/APPSwe+/- double transgenic (DTg) mice exhibited exacerbated T2D-like pathology as seen in elevated hyperglycemia compared to controls; in addition, IAPP levels in the pancreas are highest compared to controls. Moreover, IAPP+/+/APPSwe+/- animals demonstrate abundant plaque formation and greater plaque density in cortical and hippocampal areas in comparison to controls. Indeed, IAPP+/+/APPSwe+/- exhibit a colocalization of both misfolded proteins in cerebral plaques suggesting IAPP may directly interact with Aβ and aggravate AD pathology. In conclusion, these studies suggest that cross-seeding between IAPP and Aβ may occur, and that these protein aggregates exacerbate and accelerate disease pathology, respectively. Further mechanistic studies are necessary to determine how these two proteins interact and aggravate both pancreatic and brain pathologies