Faculty Bibliography

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder most commonly associated with repetitive traumatic brain injury (TBI) and characterized by the presence of neurofibrillary tangles of tau protein, known as a tauopathy. Currently, the diagnosis of CTE can only be definitively established postmortem. However, a new positron emission tomography (PET) ligand, [18F]T807/AV1451, may provide the antemortem detection of tau aggregates, and thus various tauopathies, including CTE. Our goal was to examine [18F]T807/AV1451 retention in athletes with neuropsychiatric symptoms associated with a history of multiple concussions. Here we report a 39-year-old retired National Football League player who suffered 22 concussions and manifested progressive neuropsychiatric symptoms. Emotional lability and irritability were the chief complaints. Serial neuropsychological exams revealed a decline in executive functioning, processing speed and fine motor skills. Naming was below average but other cognitive functions were preserved. Structural analysis of longitudinally acquired magenetic resonance imaging scans revealed cortical thinning in the left frontal and lateral temporal areas, as well as volume loss in the basal ganglia. PET with [18F]florbetapir was negative for amyloidosis. The [18F]T807/AV1451 PET showed multifocal areas of retention at the cortical gray matter-white matter junction, a distribution considered pathognomonic for CTE. [18F]T807/AV1451 standard uptake value (SUV) analysis showed increased uptake (SUVr⩾1.1) in bilateral cingulate, occipital, and orbitofrontal cortices, and several temporal areas. Although definitive identification of the neuropathological underpinnings basis for [18F]T807/AV1451 retention requires postmortem correlation, our data suggest that [18F]T807/AV1451 tauopathy imaging may be a promising tool to detect and diagnose CTE-related tauopathy in living subjects.

Proteins persist longer in the fossil record than DNA, but the longevity, survival mechanisms and substrates remain contested. Here, we demonstrate the role of mineral binding in preserving the protein sequence in ostrich (Struthionidae) eggshell, including from the palaeontological sites of Laetoli (3.8 Ma) and Olduvai Gorge (1.3 Ma) in Tanzania. By tracking protein diagenesis back in time we find consistent patterns of preservation, demonstrating authenticity of the surviving sequences. Molecular dynamics simulations of struthiocalcin-1 and -2, the dominant proteins within the eggshell, reveal that distinct domains bind to the mineral surface. It is the domain with the strongest calculated binding energy to the calcite surface that is selectively preserved. Thermal age calculations demonstrate that the Laetoli and Olduvai peptides are 50 times older than any previously authenticated sequence (equivalent to ~16 Ma at a constant 10°C).

The mechanical properties of living tissues have a significant impact on cell differentiation, but remain unexplored in the context of myelin formation and repair. In the PNS, the extracellular matrix (ECM) incorporates a basal lamina significantly denser than the loosely organized CNS matrix. Inhibition of non-muscle myosin II (NMII) enhances central but impairs peripheral myelination and NMII has been implicated in cellular responses to changes in the elasticity of the ECM. To directly evaluate whether mechanotransduction plays a role in glial cell differentiation, we cultured Schwann cells (SC) and oligodendrocytes (OL) on matrices of variable elastic modulus, mimicking either their native environment or conditions found in injured tissue. We found that a rigid, lesion-like matrix inhibited branching and differentiation of OL in NMII-dependent manner. By contrast, SC developed normally in both soft and stiffer matrices. Although SC differentiation was not significantly affected by changes in matrix stiffness alone, we found that expression of Krox-20 was potentiated on rigid matrices at high laminin concentration. These findings are relevant to the design of biomaterials to promote healing and regeneration in both CNS and PNS, via transplantation of glial progenitors or the implantation of tissue scaffolds.

Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated gammadeltaT cell population, which constituted approximately 40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of gammadeltaT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of gammadeltaT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of alphabetaT cells. Although alphabetaT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon gammadeltaT cell ablation. PDA-infiltrating gammadeltaT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in gammadeltaT cells enhanced CD4+ and CD8+ T cell infiltration and immunogenicity and induced tumor protection suggesting that gammadeltaT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe gammadeltaT cells as central regulators of effector T cell activation in cancer via novel cross-talk.

BACKGROUND:The mouse cerebellum (Cb) has a remarkably complex foliated three-dimensional (3D) structure, but a stereotypical cytoarchitecture and local circuitry. Little is known of the cellular behaviors and genes that function during development to determine the foliation pattern. In the anteroposterior axis the mammalian cerebellum is divided by lobules with distinct sizes, and the foliation pattern differs along the mediolateral axis defining a medial vermis and two lateral hemispheres. In the vermis, lobules are further grouped into four anteroposterior zones (anterior, central, posterior and nodular zones) based on genetic criteria, and each has distinct lobules. Since each cerebellar afferent group projects to particular lobules and zones, it is critical to understand how the 3D structure of the Cb is acquired. During cerebellar development, the production of granule cells (gcs), the most numerous cell type in the brain, is required for foliation. We hypothesized that the timing of gc accumulation is different in the four vermal zones during development and contributes to the distinct lobule morphologies. METHODS AND RESULTS:In order to test this idea, we used genetic inducible fate mapping to quantify accumulation of gcs in each lobule during the first two postnatal weeks in mice. The timing of gc production was found to be particular to each lobule, and delayed in the central zone lobules relative to the other zones. Quantification of gc proliferation and differentiation at three time-points in lobules representing different zones, revealed the delay involves a later onset of maximum differentiation and prolonged proliferation of gc progenitors in the central zone. Similar experiments in Engrailed mutants (En1 (-/+) ;En2 (-/-) ), which have a smaller Cb and altered foliation pattern preferentially outside the central zone, showed that gc production, proliferation and differentiation are altered such that the differences between zones are attenuated compared to wild-type mice. CONCLUSIONS:Our results reveal that gc production is differentially regulated in each zone of the cerebellar vermis, and our mutant analysis indicates that the dynamics of gc production plays a role in determining the 3D structure of the Cb.

In this issue of Neuron, Yuzwa et al. (2016) identify secreted factors that influence the cell fates of embryonic neural progenitor cells. Surprisingly, the major contributors are trophic factors from the GDNF family and a cytokine, interferon-gamma. Advanced analysis of proteomic and transcriptome data discovered ligand receptors that influence cell-cell communication.

Advances in financial engineering are radically reshaping the biomedical marketplace. For instance, new methods of pooling diversified drug development programs by placing them in a special purpose vehicle (SPV) have been proposed to create a securitized cancer megafund allowing for debt and equity participation. In this study, we perform theoretical and numerical simulations that highlight the role of empirical validation of the projects comprising a cancer megafund. We quantify the degree to which the deliberately designed structure of derivatives and investments is key to its liquidity. Research megafunds with comprehensive in silico and laboratory validation protocols and ability to issue both debt, and equity as well as hybrid financial products may enable conservative investors including pension funds and sovereign government funds to profit from unique securitization opportunities. Thus, while hedging investor's longevity risk, such well-validated megafunds will contribute to health, well being and longevity of the global population.

Rhomboids are ubiquitous intramembrane serine proteases involved in various signaling pathways. While the high-resolution structures of the Escherichia coli rhomboid GlpG with various inhibitors revealed an active site comprised of a serine-histidine dyad and an extensive oxyanion hole, the molecular details of rhomboid catalysis were unclear because substrates are unknown for most of the family members. Here we used the only known physiological pair of AarA rhomboid with its psTatA substrate to decipher the contribution of catalytically important residues to the reaction rate enhancement. An MD-refined homology model of AarA was used to identify residues important for catalysis. We demonstrated that the AarA active site geometry is strict and intolerant to alterations. We probed the roles of H83 and N87 oxyanion hole residues and determined that substitution of H83 either abolished AarA activity or reduced the transition state stabilization energy (DeltaDeltaGdouble dagger) by 3.1 kcal/mol; substitution of N87 decreased DeltaDeltaGdouble dagger by 1.6-3.9 kcal/mol. Substitution M154, a residue conserved in most rhomboids that stabilizes the catalytic general base, to tyrosine, provided insight into the mechanism of nucleophile generation for the catalytic dyad. This study provides a quantitative evaluation of the role of several residues important for hydrolytic efficiency and oxyanion stabilization during intramembrane proteolysis.

In a typical workplace, organizational policies and their compliance requirements set the stage upon which the behavioral patterns of individual agents evolve. The agents"™ personal utilities, access to information, and strategic deceptions shape the signaling systems of an intricate information-asymmetric game, thus mystifying assessment and management of organizational risks, which are primarily due to unintentional insider threats. Compliance games, as discussed here, model a rudimentary version of this signaling game between a sender (employee) and a receiver (organization). The analysis of these games"™ equilibria as well as their dynamics in repeated game settings illuminate the effectiveness or risks of an organizational policy. These questions are explored via a repeated and agent-based simulation of compliance signaling games, leading to the following: (1) a simple but broadly applicable model for interactions between sender agents (employees) and receiver agents (principals in the organization), (2) an investigation of how the game theoretic approach yields the plausible dynamics of compliance, and (3) design of experiments to estimate parameters of the systems: evolutionary learning rates of agents, the efficacy of auditing using a trembling hand strategy, effects of non-stationary and multiple principal agents, and ultimately, the robustness of the system under perturbation of various related parameters (costs, penalties, benefits, etc.). The paper concludes with a number of empirical studies, illustrating a battery of compliance games under varying environments designed to investigate agent based learning, system control, and optimization. The studies indicate how agents through limited interactions described by behavior traces may learn and optimize responses to a stationary defense, expose sensitive parameters and emergent properties and indicate the possibility of controlling interventions which actuate game parameters. We believe that the work is of practical importance"”for example, in constraining the vulnerability surfaces arising from compliance games.

Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants that are utilized to treatmajor depressive disorders and anxiety disorders; SSRIs are the most widely used antidepressants worldwide.3 Past literature on SSRIs have documented that use of SSRIs reduce bone formation thus increasing the risk of bone fracture. Inhibiting the reuptake of 5-HTs results in increased osteoclast differentiation and inhibition of osteoblast proliferation, leading to an overall decrease in bone mass and bone mineral density. 1Recent studies have suggested that use of SSRIs is associated with increased risk of dental implant failure, although other studies involving bone loss and remodeling have reported conflicting results. In addition to SSRIs, proton- proton inhibitors and anti-epileptic drugs have also been implicated in impaired bone remodeling. We conducted a retrospective study on patients who completed dental implant therapy from December 2007 to January 2016 at a single institution. A total of 510 dental implants (167 implants placed in 29 patients using SSRIs) placed in 108 male patients were used to assess the risk associated with the use of SSRI. The data was analyzed with a multivariate analysis and linear regression model. Osseointegration is defined as a direct structural and functional connection between ordered living bone and the surface of a load-carrying implant, that is critical for implant stability.2 In order for implants to be considered successful, they must be fully osseointegrated with the bone and provide function. Implant failure is defined as presenting with one or more of the following: clinical signs of mobility, pain, infection, total loss of implant, radiographic bone loss and/or peri-apical pathology. The results of our study show that in patients taking an SSRI at the time of dental implant therapy, 10 implants failed and 157 were successful (5.99% failure rate), while in those who were not taking an SSRI, 20 implants failed and 323 were successful (5.83% failure rate). We found no association between SSRI and dental implant failure risk (RR = 1.03; 95% confidence interval, 0.4918-2.1443; p = 0.9436). A secondary outcome that was associated with increased failure rate was smoking habits (p = 0.03), which is in agreement with previous studies. Additionally, we did not find a dose-dependent risk of dental implant failure in patients who were taking a low-moderate vs. moderate- high dose of SSRIs (RR = 1.91, 95% confidence interval, 0.4201 -8.6981; p = 0.40) The study assessed the use of proton- pump inhibitors and anti-epileptic drugs in the above patients, demonstrating that there was no associated risk of implant failure (p =0.93; p = 0.84, respectively). Our results conclude that treatment with SSRIs is not associated with an increased failure rate of osseointegration of dental implants, which is not in agreement with previously reported studies. 4