T cell avidity and tumor recognition: implications and therapeutic strategies

In the last two decades, great advances have been made studying the immune response to human tumors. The identification of protein antigens from cancer cells and better techniques for eliciting antigen specific T cell responses in vitro and in vivo have led to improved understanding of tumor recognition by T cells. Yet, much remains to be learned about the intricate details of T cell – tumor cell interactions. Though the strength of interaction between T cell and target is thought to be a key factor influencing the T cell response, investigations of T cell avidity, T cell receptor (TCR) affinity for peptide-MHC complex, and the recognition of peptide on antigen presenting targets or tumor cells reveal complex relationships. Coincident with these investigations, therapeutic strategies have been developed to enhance tumor recognition using antigens with altered peptide structures and T cells modified by the introduction of new antigen binding receptor molecules. The profound effects of these strategies on T cell – tumor interactions and the clinical implications of these effects are of interest to both scientists and clinicians. In recent years, the focus of much of our work has been the avidity and effector characteristics of tumor reactive T cells. Here we review concepts and current results in the field, and the implications of therapeutic strategies using altered antigens and altered effector T cells

Assessing uncertainties in scattering correction algorithms for reflective tube absorption measurements made with a WET Labs ac-9

In situ absorption measurements collected with a WET Labs ac-9 employing a reflective tube approach were scatter corrected using several possible methods and compared to reference measurements made by a PSICAM to assess performance. Overall, two correction methods performed best for the stations sampled: one using an empirical relationship between the ac-9 and PSICAM to derive the scattering error (ε) in the nearinfrared (NIR), and one where ε was independently derived from concurrent measurements of the volume scattering function (VSF). Application of the VSF-based method may be more universally applicable, although difficult to routinely apply because of the lack of commercially available VSF instrumentation. The performance of the empirical approach is encouraging as it relies only on the ac meter measurement and may be readily applied to historical data, although there are inevitably some inherent assumptions about particle composition that hinder universal applicability. For even the best performing methods, residual errors of 20% or more were commonly observed for many water types. For clear ocean waters, a conventional baseline subtraction with the assumption of negligible near-IR absorption performed as well or better than the above methods because propagated uncertainties were lower than observed with the proportional method

Unusual cage rearrangements in 10-vertex nido-5,6-dicarbaborane derivatives : An interplay between theory and experiment

The reaction between selected X-nido-5,6-C2B8H11 compounds (where X = Cl, Br, I) and "Proton Sponge" [PS; 1,8-bis(dimethylamino)naphthalene], followed by acidification, results in extensive rearrangement of all cage vertices. Specifically, deprotonation of 7-X-5,6-C2B8H11 compounds with one equivalent of PS in hexane or CH2Cl2 at ambient temperature led to a 7 → 10 halogen rearrangement, forming a series of PSH+[10-X-5,6-C2B8H10]- salts. Reprotonation using concentrated H2SO4 in CH2Cl2 generates a series of neutral carbaboranes 10-X-5,6-C2B8H11, with the overall 7 → 10 conversion being 75%, 95%, and 100% for X = Cl, Br, and I, respectively. Under similar conditions, 4-Cl-5,6-C2B8H11 gave ∼66% conversion to 3- Cl-5,6-C2B8H11. Since these rearrangements could not be rationalized using the Bvertex swing mechanism, new cage rearrangement mechanisms, which are substantiated using DFT calculations, have been proposed. Experimental 11B NMR chemical shifts are well reproduced by the computations; as expected δ(11B) for B(10) atoms in derivatives with X = Br and I are heavily affected by spin-orbit coupling

Host phylogeny, geographic overlap, and roost sharing shape parasite communities in European bats

How multitrophic relationships between wildlife communities and their ectoparasitic vectors interact to shape the diversity of vector-borne microorganisms is poorly understood. Nested levels of dependence among microbes, vectors, and vertebrate hosts may have complicated effects on both microbial community assembly and evolution. We examined Bartonella sequences from European bats and their ectoparasites with a combination of network analysis, Bayesian phylogenetics, tip-association and cophylogeny tests, and linear regression to understand the ecological and evolutionary processes that shape parasite communities. We detected seven batectoparasite-Bartonella communities that can be differentiated based on bat families and roosting patterns. Tips of the Bartonella tree were significantly clustered by host taxonomy and geography. We also found significant evidence of evolutionary congruence between bat host and Bartonella phylogenies, indicating that bacterial species have evolved to infect related bat species. Exploring these ecological and evolutionary associations further, we found that sharing of Bartonella species among bat hosts was strongly associated with host phylogenetic distance and roost sharing and less strongly with geographic range overlap. Ectoparasite sharing between hosts was strongly predicted by host phylogenetic distance, roost sharing, and geographic overlap but had no additive effect on Bartonella sharing. Finally, historical Bartonella host-switching was more frequent for closely related bats after accounting for sampling bias among bat species. This study helps to disentangle the complex ecology and evolution of Bartonella bacteria in bat species and their arthropod vectors. Our work provides insight into the important mechanisms that partition parasite communities among hosts, particularly the effect of host phylogeny and roost sharing, and could help to elucidate the evolutionary patterns of other diverse vector-borne microorganisms

Piecewise Parabolic Method on a Local Stencil for Magnetized Supersonic Turbulence Simulation

Stable, accurate, divergence-free simulation of magnetized supersonic turbulence is a severe test of numerical MHD schemes and has been surprisingly difficult to achieve due to the range of flow conditions present. Here we present a new, higher order-accurate, low dissipation numerical method which requires no additional dissipation or local "fixes" for stable execution. We describe PPML, a local stencil variant of the popular PPM algorithm for solving the equations of compressible ideal magnetohydrodynamics. The principal difference between PPML and PPM is that cell interface states are evolved rather that reconstructed at every timestep, resulting in a compact stencil. Interface states are evolved using Riemann invariants containing all transverse derivative information. The conservation laws are updated in an unsplit fashion, making the scheme fully multidimensional. Divergence-free evolution of the magnetic field is maintained using the higher order-accurate constrained transport technique of Gardiner and Stone. The accuracy and stability of the scheme is documented against a bank of standard test problems drawn from the literature. The method is applied to numerical simulation of supersonic MHD turbulence, which is important for many problems in astrophysics, including star formation in dark molecular clouds. PPML accurately reproduces in three-dimensions a transition to turbulence in highly compressible isothermal gas in a molecular cloud model. The low dissipation and wide spectral bandwidth of this method make it an ideal candidate for direct turbulence simulations.Comment: 28 pages, 18 figure

Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football

IMPORTANCE: Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE). OBJECTIVE: To determine the neuropathological and clinical features of deceased football players with CTE. DESIGN, SETTING, AND PARTICIPANTS: Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history. EXPOSURES: Participation in American football at any level of play. MAIN OUTCOMES AND MEASURES: Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia. RESULTS: Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre–high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. CONCLUSIONS AND RELEVANCE: In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.This study received support from NINDS (grants U01 NS086659, R01 NS078337, R56 NS078337, U01 NS093334, and F32 NS096803), the National Institute on Aging (grants K23 AG046377, P30AG13846 and supplement 0572063345-5, R01 AG1649), the US Department of Defense (grant W81XWH-13-2-0064), the US Department of Veterans Affairs (I01 CX001038), the Veterans Affairs Biorepository (CSP 501), the Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (grant B6796-C), the Department of Defense Peer Reviewed Alzheimer’s Research Program (grant 13267017), the National Operating Committee on Standards for Athletic Equipment, the Alzheimer’s Association (grants NIRG-15-362697 and NIRG-305779), the Concussion Legacy Foundation, the Andlinger Family Foundation, the WWE, and the NFL

Hydrodynamical simulations of the decay of high-speed molecular turbulence. I. Dense molecular regions

We present the results from three dimensional hydrodynamical simulations of decaying high-speed turbulence in dense molecular clouds. We compare our results, which include a detailed cooling function, molecular hydrogen chemistry and a limited C and O chemistry, to those previously obtained for decaying isothermal turbulence. After an initial phase of shock formation, power-law decay regimes are uncovered, as in the isothermal case. We find that the turbulence decays faster than in the isothermal case because the average Mach number remains higher, due to the radiative cooling. The total thermal energy, initially raised by the introduction of turbulence, decays only a little slower than the kinetic energy. We discover that molecule reformation, as the fast turbulence decays, is several times faster than that predicted for a non-turbulent medium. This is caused by moderate speed shocks which sweep through a large fraction of the volume, compressing the gas and dust. Through reformation, the molecular density and molecular column appear as complex patterns of filaments, clumps and some diffuse structure. In contrast, the molecular fraction has a wider distribution of highly distorted clumps and copious diffuse structure, so that density and molecular density are almost identically distributed during the reformation phase. We conclude that molecules form in swept-up clumps but effectively mix throughout via subsequent expansions and compressions.Comment: 12 pages, 12 figures; For a version of the article with higher resolution figures, see http://star.arm.ac.uk/preprints/381.p

Kinetic Energy Decay Rates of Supersonic and Super-Alfvenic Turbulence in Star-Forming Clouds

We present numerical studies of compressible, decaying turbulence, with and without magnetic fields, with initial rms Alfven and Mach numbers ranging up to five, and apply the results to the question of the support of star-forming interstellar clouds of molecular gas. We find that, in 1D, magnetized turbulence actually decays faster than unmagnetized turbulence. In all the regimes that we have studied 3D turbulence-super-Alfvenic, supersonic, sub-Alfvenic, and subsonic-the kinetic energy decays as (t-t0)^(-x), with 0.85 < x < 1.2. We compared results from two entirely different algorithms in the unmagnetized case, and have performed extensive resolution studies in all cases, reaching resolutions of 256^3 zones or 350,000 particles. We conclude that the observed long lifetimes and supersonic motions in molecular clouds must be due to external driving, as undriven turbulence decays far too fast to explain the observations.Comment: Submitted to Phys. Rev. Letters, 29 Nov. 1997. 10 pages, 2 figures, also available from http://www.mpia-hd.mpg.de/theory/preprints.html#maclo

Host Phylogeny, Geographic Overlap, and Roost Sharing Shape Parasite Communities in European Bats

How multitrophic relationships between wildlife communities and their ectoparasitic vectors interact to shape the diversity of vector-borne microorganisms is poorly understood. Nested levels of dependence among microbes, vectors, and vertebrate hosts may have complicated effects on both microbial community assembly and evolution. We examined Bartonella sequences from European bats and their ectoparasites with a combination of network analysis, Bayesian phylogenetics, tip-association and cophylogeny tests, and linear regression to understand the ecological and evolutionary processes that shape parasite communities. We detected seven bat–ectoparasite–Bartonella communities that can be differentiated based on bat families and roosting patterns. Tips of the Bartonella tree were significantly clustered by host taxonomy and geography. We also found significant evidence of evolutionary congruence between bat host and Bartonella phylogenies, indicating that bacterial species have evolved to infect related bat species. Exploring these ecological and evolutionary associations further, we found that sharing of Bartonella species among bat hosts was strongly associated with host phylogenetic distance and roost sharing and less strongly with geographic range overlap. Ectoparasite sharing between hosts was strongly predicted by host phylogenetic distance, roost sharing, and geographic overlap but had no additive effect on Bartonella sharing. Finally, historical Bartonella host-switching was more frequent for closely related bats after accounting for sampling bias among bat species. This study helps to disentangle the complex ecology and evolution of Bartonella bacteria in bat species and their arthropod vectors. Our work provides insight into the important mechanisms that partition parasite communities among hosts, particularly the effect of host phylogeny and roost sharing, and could help to elucidate the evolutionary patterns of other diverse vector-borne microorganisms