Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome

X-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency characterized by increased susceptibility to Epstein-Barr virus (EBV). In affected males, primary EBV infection leads to the uncontrolled proliferation of virus-containing B cells and reactive cytotoxic T cells, often culminating in the development of high-grade lymphoma. The XLP gene has been mapped to chromosome band Xq25 through linkage analysis and the discovery of patients harboring large constitutional genomic deletions. We describe here the presence of small deletions and intragenic mutations that specifically disrupt a gene named DSHP in 6 of 10 unrelated patients with XLP. This gene encodes a predicted protein of 128 amino acids composing a single SH2 domain with extensive homology to the SH2 domain of SHIP, an inositol polyphosphate 5-phosphatase that functions as a negative regulator of lymphocyte activation. DSHP is expressed in transformed T cell lines and is induced following in vitro activation of peripheral blood T lymphocytes. Expression of DSHP is restricted in vivo to lymphoid tissues, and RNA in situ hybridization demonstrates DSHP expression in activated T and B cell regions of reactive lymph nodes and in both T and B cell neoplasms. These observations confirm the identity of DSHP as the gene responsible for XLP, and suggest a role in the regulation of lymphocyte activation and proliferation. Induction of DSHP may sustain the immune response by interfering with SHIP-mediated inhibition of lymphocyte activation, while its inactivation in XLP patients results in a selective immunodeficiency to EBV.

Evaluation of La1−xSrxMnO3 (0 ≤ x < 0.4) synthesised via a modified sol–gel method as mediators for magnetic fluid hyperthermia

A range of lanthanum strontium manganates (La1−xSrxMnO3–LSMO) where 0 ≤ x < 0.4 were prepared using a modified peroxide sol–gel synthesis method. The magnetic nanoparticle (MNP) clusters obtained for each of the materials were characterised using scanning electron microscopy (SEM), X-ray powder diffraction (XRD) and infra-red (IR) spectroscopy in order to confirm the crystalline phases, crystallite size and cluster morphology. The magnetic properties of the materials were assessed using the Superconducting quantum interference device (SQUID) to evaluate the magnetic susceptibility, Curie temperature (Tc) and static hysteretic losses. Induction heating experiments also provided an insight into the magnetocaloric effect for each material. The specific absorption rate (SAR) of the materials was evaluated experimentally and via numerical simulations. The magnetic properties and heating data were linked with the crystalline structure to make predictions with respect to the best LSMO composition for mild hyperthermia (41 °C ≤ T ≤ 46 °C). La0.65Sr0.35MnO3, with crystallite diameter of 82.4 nm, (agglomerate size of ∼10 μm), Tc of 89 °C and SAR of 56 W gMn−1 at a concentration 10 mg mL−1 gave the optimal induction heating results (Tmax of 46.7 °C) and was therefore deemed as most suitable for the purposes of mild hyperthermia, vide infra.

Tumor suppressor Ras-association domain family 1 isoform A is a novel regulator of cardiac hypertrophy

BACKGROUND: Ras signaling regulates a number of important processes in the heart, including cell growth and hypertrophy. Although it is known that defective Ras signaling is associated with Noonan, Costello, and other syndromes that are characterized by tumor formation and cardiac hypertrophy, little is known about factors that may control it. Here we investigate the role of Ras effector Ras-association domain family 1 isoform A (RASSF1A) in regulating myocardial hypertrophy.

METHODS AND RESULTS: A significant downregulation of RASSF1A expression was observed in hypertrophic mouse hearts, as well as in failing human hearts. To further investigate the role of RASSF1A in cardiac (patho)physiology, we used RASSF1A knock-out (RASSF1A(-)(/)(-)) mice and neonatal rat cardiomyocytes with adenoviral overexpression of RASSF1A. Ablation of RASSF1A in mice significantly enhanced the hypertrophic response to transverse aortic constriction (64.2% increase in heart weight/body weight ratio in RASSF1A(-)(/)(-) mice compared with 32.4% in wild type). Consistent with the in vivo data, overexpression of RASSF1A in cardiomyocytes markedly reduced the cellular hypertrophic response to phenylephrine stimulation. Analysis of molecular signaling events in isolated cardiomyocytes indicated that RASSF1A inhibited extracellular regulated kinase 1/2 activation, likely by blocking the binding of Raf1 to active Ras.

CONCLUSIONS: Our data establish RASSF1A as a novel inhibitor of cardiac hypertrophy by modulating the extracellular regulated kinase 1/2 pathway.

Picosecond metrology of laser-driven proton bursts

Tracking primary radiation-induced processes in matter requires ultrafast sources and high precision timing. While compact laser-driven ion accelerators are seeding the development of novel high instantaneous flux applications, combining the ultrashort ion and laser pulse durations with their inherent synchronicity to trace the real-time evolution of initial damage events has yet to be realized. Here we report on the absolute measurement of proton bursts as short as 3.5±0.7 ps from laser solid target interactions for this purpose. Our results verify that laser-driven ion acceleration can deliver interaction times over a factor of hundred shorter than those of state-of-the-art accelerators optimized for high instantaneous flux. Furthermore, these observations draw ion interaction physics into the field of ultrafast science, opening the opportunity for quantitative comparison with both numerical modelling and the adjacent fields of ultrafast electron and photon interactions in matter.

Rocking behaviour of multi-block columns subjected to pulse-type ground motion accelerations

Ancient columns, made with a variety of materials such as marble, granite, stone or masonry are an important part of the
European cultural heritage. In particular columns of ancient temples in Greece and Sicily which support only the architrave are
characterized by small axial load values. This feature together with the slenderness typical of these structural members clearly
highlights as the evaluation of the rocking behaviour is a key aspect of their safety assessment and maintenance. It has to be noted
that the rocking response of rectangular cross-sectional columns modelled as monolithic rigid elements, has been widely investigated
since the first theoretical study carried out by Housner (1963). However, the assumption of monolithic member, although being
widely used and accepted for practical engineering applications, is not valid for more complex systems such as multi-block columns
made of stacked stone blocks, with or without mortar beds. In these cases, in fact, a correct analysis of the system should consider
rocking and sliding phenomena between the individual blocks of the structure. Due to the high non-linearity of the problem, the
evaluation of the dynamic behaviour of multi-block columns has been mostly studied in the literature using a numerical approach
such as the Discrete Element Method (DEM). This paper presents an introductory study about a proposed analytical-numerical
approach for analysing the rocking behaviour of multi-block columns subjected to a sine-pulse type ground motion. Based on the
approach proposed by Spanos (2001) for a system made of two rigid blocks, the Eulero-Lagrange method to obtain the motion
equations of the system is discussed and numerical applications are performed with case studies reported in the literature and with a
real acceleration record. The rocking response of single block and multi-block columns is compared and considerations are made
about the overturning conditions and on the effect of forcing function’s frequency.
.

Real-space grids and the Octopus code as tools for the development of new simulation approaches for electronic systems

Real-space grids are a powerful alternative for the simulation of electronic systems. One of the main advantages of the approach is the flexibility and simplicity of working directly in real space where the different fields are discretized on a grid, combined with competitive numerical performance and great potential for parallelization. These properties constitute a great advantage at the time of implementing and testing new physical models. Based on our experience with the Octopus code, in this article we discuss how the real-space approach has allowed for the recent development of new ideas for the simulation of electronic systems. Among these applications are approaches to calculate response properties, modeling of photoemission, optimal control of quantum systems, simulation of plasmonic systems, and the exact solution of the Schrödinger equation for low-dimensionality systems.

Nonequilibrium processes from generalized Langevin equations: Realistic nanoscale systems connected to two thermal baths

We extend the generalized Langevin equation (GLE) method [L. Stella, C. D. Lorenz, and L. Kantorovich, Phys. Rev. B 89, 134303 (2014)] to model a central classical region connected to two realistic thermal baths at two different temperatures. In such nonequilibrium conditions a heat flow is established, via the central system, in between the two baths. The GLE-2B (GLE two baths) scheme permits us to have a realistic description of both the dissipative central system and its surrounding baths. Following the original GLE approach, the extended Langevin dynamics scheme is modified to take into account two sets of auxiliary degrees of freedom corresponding to the mapping of the vibrational properties of each bath. These auxiliary variables are then used to solve the non-Markovian dissipative dynamics of the central region. The resulting algorithm is used to study a model of a short Al nanowire connected to two baths. The results of the simulations using the GLE-2B approach are compared to the results of other simulations that were carried out using standard thermostatting approaches (based on Markovian Langevin and Nosé-Hoover thermostats). We concentrate on the steady-state regime and study the establishment of a local temperature profile within the system. The conditions for obtaining a flat profile or a temperature gradient are examined in detail, in agreement with earlier studies. The results show that the GLE-2B approach is able to treat, within a single scheme, two widely different thermal transport regimes, i.e., ballistic systems, with no temperature gradient, and diffusive systems with a temperature gradient.