Elevated neoantigen levels in tumors with somatic mutations in the HLA-A, HLA-B, HLA-C and B2M genes.

BackgroundThe major histocompatibility complex class I (MHC-I) molecule is a protein complex that displays intracellular peptides to T cells, allowing the immune system to recognize and destroy infected or cancerous cells. MHC-I is composed of a highly polymorphic HLA-encoded alpha chain that binds the peptide and a Beta-2-microglobulin (B2M) protein that acts as a stabilizing scaffold. HLA mutations have been implicated as a mechanism of immune evasion during tumorigenesis, and B2M is considered a tumor suppressor gene. However, the implications of somatic HLA and B2M mutations have not been fully explored in the context of antigen presentation via the MHC-I molecule during tumor development. To understand the effect that B2M and HLA MHC-I molecule mutations have on mutagenesis, we analyzed the accumulation of mutations in patients from The Cancer Genome Atlas according to their MHC-I molecule mutation status.ResultsSomatic B2M and HLA mutations in microsatellite stable tumors were associated with higher overall mutation burden and a larger fraction of HLA-binding neoantigens when compared to B2M and HLA wild type tumors. B2M and HLA mutations were highly enriched in patients with microsatellite instability. B2M mutations tended to occur relatively early during patients' respective tumor development, whereas HLA mutations were either early or late events. In addition, B2M and HLA mutated patients had higher levels of immune infiltration by natural killer and CD8+ T cells and higher levels of cytotoxicity.ConclusionsOur findings add to a growing body of evidence that somatic B2M and HLA mutations are a mechanism of immune evasion by demonstrating that such mutations are associated with a higher load of neoantigens that should be presented via MHC-I

On the nonlinear dynamics of the traveling-wave solutions of the Serre system

We numerically study nonlinear phenomena related to the dynamics of traveling wave solutions of the Serre equations including the stability, the persistence, the interactions and the breaking of solitary waves. The numerical method utilizes a high-order finite-element method with smooth, periodic splines in space and explicit Runge-Kutta methods in time. Other forms of solutions such as cnoidal waves and dispersive shock waves are also considered. The differences between solutions of the Serre equations and the Euler equations are also studied.Comment: 28 pages, 20 figures, 3 tables, 33 references. Other author's papers can be downloaded at http://www.denys-dutykh.com

Voltage-controlled wavelength conversion by terahertz electro-optic modulation in double quantum wells

An undoped double quantum well (DQW) was driven with a terahertz (THz) electric field of frequency \omega_{THz} polarized in the growth direction, while simultaneously illuminated with a near-infrared (NIR) laser at frequency \omega_{NIR}. The intensity of NIR upconverted sidebands \omega_{sideband}=\omega_{NIR} + \omega_{THz} was maximized when a dc voltage applied in the growth direction tuned the excitonic states into resonance with both the THz and NIR fields. There was no detectable upconversion far from resonance. The results demonstrate the possibility of using gated DQW devices for all-optical wavelength shifting between optical communication channels separated by up to a few THz.Comment: 3 pages, 6 figures. Figures 5 and 6 are JPEG files, figures/fig5.jpg and fig6.jp

Transformation of Cs-IONSIV® into a ceramic wasteform by hot isostatic pressing

A simple method to directly convert Cs-exchanged IONSIV® IE-911 into a ceramic wasteform by hot isostatic pressing (1100 °C/190 MPa/2 hr) is presented. Two major Cs-containing phases, Cs2TiNb6O18 and Cs2ZrSi6O15, and a series of mixed oxides form. The microstructure and phase assemblage of the samples as a function of Cs content were examined using XRD, XRF, SEM and TEM/EDX. The chemical aqueous durability of the materials was investigated using the MCC-1 and PCT-B standard test methods. For HIPed Cs-IONSIV® samples, the MCC-1 normalised release rates of Cs were <1.57 × 10−1 g m−2 d−1 at 0–28 days, and <3.78 × 10−2 g m−2 d−1 for PCT-B at 7 days. The low rates are indicative of a safe long-term immobilisation matrix for Cs formed directly from spent IONSIV®. It was also demonstrated that the phase formation can be altered by adding Ti metal due to a controlled redox environment

Strong-field terahertz-optical mixing in excitons

Driving a double-quantum-well excitonic intersubband resonance with a terahertz (THz) electric field of frequency \omega_{THz} generated terahertz optical sidebands \omega=\omega_{THz}+\omega_{NIR} on a weak NIR probe. At high THz intensities, the intersubband dipole energy which coupled two excitons was comparable to the THz photon energy. In this strong-field regime the sideband intensity displayed a non-monotonic dependence on the THz field strength. The oscillating refractive index which gives rise to the sidebands may be understood by the formation of Floquet states, which oscillate with the same periodicity as the driving THz field.Comment: 4 pages, 6 figure

On the Galilean invariance of some dispersive wave equations

Surface water waves in ideal fluids have been typically modeled by asymptotic approximations of the full Euler equations. Some of these simplified models lose relevant properties of the full water wave problem. One of them is the Galilean symmetry, which is not present in important models such as the BBM equation and the Peregrine (Classical Boussinesq) system. In this paper we propose a mechanism to modify the above mentioned classical models and derive new, Galilean invariant models. We present some properties of the new equations, with special emphasis on the computation and interaction of their solitary-wave solutions. The comparison with full Euler solutions shows the relevance of the preservation of Galilean invariance for the description of water waves.Comment: 29 pages, 13 figures, 2 tables, 71 references. Other author papers can be downloaded at http://www.denys-dutykh.com

Cancellous bone and theropod dinosaur locomotion. Part II—a new approach to inferring posture and locomotor biomechanics in extinct tetrapod vertebrates

This paper is the second of a three-part series that investigates the architecture of cancellous bone in the main hindlimb bones of theropod dinosaurs, and uses cancellous bone architectural patterns to infer locomotor biomechanics in extinct non-avian species. Cancellous bone is widely known to be highly sensitive to its mechanical environment, and therefore has the potential to provide insight into locomotor biomechanics in extinct tetrapod vertebrates such as dinosaurs. Here in Part II, a new biomechanical modelling approach is outlined, one which mechanistically links cancellous bone architectural patterns with three-dimensional musculoskeletal and finite element modelling of the hindlimb. In particular, the architecture of cancellous bone is used to derive a single ‘characteristic posture’ for a given species—one in which bone continuum-level principal stresses best align with cancellous bone fabric—and thereby clarify hindlimb locomotor biomechanics. The quasi-static approach was validated for an extant theropod, the chicken, and is shown to provide a good estimate of limb posture at around mid-stance. It also provides reasonable predictions of bone loading mechanics, especially for the proximal hindlimb, and also provides a broadly accurate assessment of muscle recruitment insofar as limb stabilization is concerned. In addition to being useful for better understanding locomotor biomechanics in extant species, the approach hence provides a new avenue by which to analyse, test and refine palaeobiomechanical hypotheses, not just for extinct theropods, but potentially many other extinct tetrapod groups as well

Direction of the polymorphic form of entacapone using an electrochemical tuneable surface template

The ability to direct the surface crystallisation of different polymorphs of entacapone by tuning the electrochemical potential of Au(100) templates is demonstrated. Under quiescent conditions, without polarization (at open circuit potential), entacapone crystallises in its stable form A on the template surface and concomitantly in its metastable form D in the bulk solution. When Au(100) is negatively polarized (-150 mV), form D is still formed in the bulk solution but the metastable form α is found to crystallise at the edges of the template. Both crystals of form A and α were observed to grow epitaxially over the Au template surface. The electrochemical templating effect is consistent with the polarisation changing the structure of the initially adsorbed layers of supersaturated solution at the template surface which directs the nuclei formation and the subsequent crystal growth processes. This study demonstrates, for the first time, the direction of polymorphic form using a low field polarized nucleation template

Cancellous bone and theropod dinosaur locomotion. Part I—an examination of cancellous bone architecture in the hindlimb bones of theropods

This paper is the first of a three-part series that investigates the architecture of cancellous (‘spongy’) bone in the main hindlimb bones of theropod dinosaurs, and uses cancellous bone architectural patterns to infer locomotor biomechanics in extinct non-avian species. Cancellous bone is widely known to be highly sensitive to its mechanical environment, and has previously been used to infer locomotor biomechanics in extinct tetrapod vertebrates, especially primates. Despite great promise, cancellous bone architecture has remained little utilized for investigating locomotion in many other extinct vertebrate groups, such as dinosaurs. Documentation and quantification of architectural patterns across a whole bone, and across multiple bones, can provide much information on cancellous bone architectural patterns and variation across species. Additionally, this also lends itself to analysis of the musculoskeletal biomechanical factors involved in a direct, mechanistic fashion. On this premise, computed tomographic and image analysis techniques were used to describe and analyse the three-dimensional architecture of cancellous bone in the main hindlimb bones of theropod dinosaurs for the first time. A comprehensive survey across many extant and extinct species is produced, identifying several patterns of similarity and contrast between groups. For instance, more stemward non-avian theropods (e.g. ceratosaurs and tyrannosaurids) exhibit cancellous bone architectures more comparable to that present in humans, whereas species more closely related to birds (e.g. paravians) exhibit architectural patterns bearing greater similarity to those of extant birds. Many of the observed patterns may be linked to particular aspects of locomotor biomechanics, such as the degree of hip or knee flexion during stance and gait. A further important observation is the abundance of markedly oblique trabeculae in the diaphyses of the femur and tibia of birds, which in large species produces spiralling patterns along the endosteal surface. Not only do these observations provide new insight into theropod anatomy and behaviour, they also provide the foundation for mechanistic testing of locomotor hypotheses via musculoskeletal biomechanical modelling