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Splice variants of CD74 differentially modulate the activity of cathepsin L (CTSL). As CD74 and CTSL participate in the pathogenesis of inflammatory diseases such as rheumatoid arthritis (RA), we determined whether splice variants of CD74 could be biomarkers of disease activity. Gene expression was measured in mice with collagen-induced arthritis using quantitative PCR (qPCR). In vitro studies using murine macrophage/DC-lineage cells determined the relative influence of macrophage phenotype on isoform expression and the potential to produce CTSL in response to TNF. CD74 splice variants were measured in human RA synovium and RA patients’ monocytes. In arthritic mice, the expression of the p41 CD74 isoform was significantly higher in severely affected paws compared with unaffected paws or the paws of naïve mice; the p41 isoform significantly correlated with the expression of TNF in arthritic paws. Compared with M2-like macrophages, M1-like macrophages expressed increased levels of CD74 and had higher expression, secretion and activity of CTSL. RA patients that responded to TNF blockade had significantly higher expression levels of CD74 in circulating monocytes after treatment, compared with non-responders. The expression of the human CD74 isoform a was significantly higher in RA synovia, compared with osteoarthritis synovia, and was associated with CSTL enzymatic activity. This study is the first to demonstrate differential expression of the CD74 p41 isoform in an auto-immune disorder and in response to therapy. The differential expression of CD74 splice variants indicates an association, and potentially a mechanistic role, in the pathogenesis of RA.

A repeated or prolonged stimulation with LPS induces in macrophage-lineage cells a refractory state known as endotoxin tolerance (ET). ET curtails inflammation and prevents tissue damage caused by sustained immune activation in sepsis. TNFα is required for ET induction and it is hypothesized that TNFα exerts its immuno-modulatory action via ET-associated molecules. In models of TNFα-driven disease, ET-associated molecules were investigated to determine their role in the progression from acute, self-limiting inflammation to chronic inflammatory disease. An in vitro model of ET was developed to evaluate the gene expression profile of ET macrophages. The ET-associated genes IRAK3, TNFAIP3 and PTPN6 were further investigated in collagen-induced arthritis (CIA). Although arthritic paws had increased macrophage-lineage cell infiltration and high expression of TLRs and TNFα, the expression of ET-associated genes was not uniformly increased. Tnfaip3 and Ptpn6 were up-regulated in arthritic paws but Irak3, a key molecule in ET which inhibits the MyD88 pathway, was expressed at a lower level than the naïve control throughout the inflammatory process. CIA was performed in IRAK3-/- mice and WT controls. In IRAK3-/- mice the disease was significantly accelerated, inflammatory gene expression was higher in paws, plasma IL1β concentration was higher and there was a decrease in the prevalence of regulatory T cells in spleen and lymph-nodes. We hypothesize that an alteration in IRAK3 gene expression or activity potentiates the development and chronicity of inflammatory disease.

Common Variable Immunodeficiency belongs to the group of rare diseases encompassing antibody deficiency syndromes of highly variable clinical presentation and outcome. The multicenter prospective study on a cohort of 224 patients with Common Variable Immunodeficiency provides an updated view of the spectrum of illnesses which occurred at the clinical onset and over a long period of follow-up (mean time: 11 years) and information on the effects of long-term immunoglobulin treatment. The mean age at the time of diagnosis was 26.6 years. Seventy-five patients were younger than 14 years of age. The mean age at the onset of symptoms was 16.9 years. This implicates with a mean diagnostic delay of 8.9 years. Respiratory tract infections were the most prominent clinical problem observed at diagnosis and during the follow-up. Intravenous immunoglobulin administration induced a significant reduction in the incidence of acute infections, mainly acute pneumonia and acute otitis. However, a progressive increase in the prevalence of patients with chronic diseases, mainly sinusitis and lung disease, was observed in all age groups, including the pediatric population. The morbidity of Common Variable Immunodeficiency due to all associated clinical conditions increased over time despite an adequate replacement with intravenous immunoglobulins. Our data stressed the need to develop international guidelines for the prevention and therapy of chronic lung disease, chronic sinusitis, chronic diarrhoea, and chronic granulomatosis in patients with humoral immunodeficiencies.

Electromagnetic and Light Scattering crosses the boundaries of many science and engineering disciplines. It is central to both fundamental and applied research in astrophysics, atmospheric physics, geophysics, materials science, nano-optics, biology, and medicine.

We study optical trapping of nanotubes and graphene. We extract the distribution of both centre-of-mass and angular fluctuations from three-dimensional tracking of these optically trapped carbon nanostructures. The optical force and torque constants are measured from auto and cross-correlation of the tracking signals. We demonstrate that nanotubes enable nanometer spatial, and femto-Newton force resolution in photonic force microscopy by accurately measuring the radiation pressure in a double frequency optical tweezers. Finally, we integrate optical trapping with Raman and photoluminescence spectroscopy demonstrating the use of a Raman and photoluminescence tweezers by investigating the spectroscopy of nanotubes and graphene flakes in solution. Experimental results are compared with calculations based on electromagnetic scattering theory.

Brownian motion is a manifestation of the fluctuation-dissipation theorem of statistical mechanics. It regulates systems in physics, biology, chemistry, and finance. We use graphene as prototype material to unravel the consequences of the fluctuation-dissipation theorem in two dimensions, by studying the Brownian motion of optically trapped graphene flakes. These orient orthogonal to the light polarization, due to the optical constants anisotropy. We explain the flake dynamics in the optical trap and measure force and torque constants from the correlation functions of the tracking signals, as well as comparing experiments with a full electromagnetic theory of optical trapping. The understanding of optical trapping of two-dimensional nanostructures gained through our Brownian motion analysis paves the way to light-controlled manipulation and all-optical sorting of biological membranes and anisotropic macromolecules.

We consider a model of diffuse cloud dust in which carbon is deposited slowly on the surfaces of silicate cores. The solid carbon is also processed by the interstellar radiation so that its optical properties change with time. The computed interstellar extinction curves (ISECs) for this model evolve in time, lie close to the observed mean ISEC for substantial periods but generate at later times significant dispersions in the far-ultraviolet (for ISECs normalized in the visual). The requirement on the carbon budget is well within that available, while essentially all the available silicon must be in the silicate cores. The variety of observed ISECs may therefore be interpreted (at least, in part) as due to evolutionary changes in a time-dependent model of interstellar dust.

We calculate the optical forces on Au and Ag nanospheres through a procedure based on the Maxwell stress tensor. We compare the theoretical and experimental force constants obtained for gold and silver nanospheres finding good agreement for all particles with r < 80nm. The trapping of the larger particles recently demonstrated in experiments is not foreseen by our purely electromagnetic theory based on fixed dielectric properties. Since the laser power produces a heating that may be large for the largest spheres, we propose a model in which the latter particles are surrounded by a steam bubble. This model foresees the trapping of these particles and the results turn out to be in reasonable agreement with the experimental data.

We calculate the radiation torque exerted by a monochromatic plane wave, either unpolarized or linearly polarized, on aggregates of spheres and investigate the stability of the resulting rotational motion. In fact, neglecting any braking momenta we calculate the component of the electromagnetic torque orthogonal to the principal axis of maximum moment of inertia through the center of mass (transverse torque), as a function of the direction of propagation of the incident field. The aggregates we study are composed of homogeneous spheres, possibly of different materials. The electromagnetic torque is calculated through the transition matrix approach along the lines of the theory reported in our recent paper [F. Borghese, P. Denti, R. Saija and M. A. Iati, Opt. Express 14, 9508 (2006)]. When the transverse component of the electromagnetic torque is small or vanishes the rotational motion driven by the component along the principal axis of inertia may be nearly stable.

Dust is an ubiquitous inhabitant of the interstellar medium, and leaves an unmistakable signature in its optical properties, and physico-chemical evolution. Although there is little direct knowledge of the true nature of interstellar dust grains, strong evidences point toward the possibility that such grains are composites of many small monomers (mainly made of silicates and carbonaceous materials). We consider two different models of fluffy dust aggregates, occurring as result of ballistic particle-cluster and cluster-cluster aggregation, and a cluster with a Gaussian-like sphere size distribution. We study the optical properties of such composite structures through the multipole fields and the Transition Matrix approach. Our results show the severe limits of applicability of the effective medium theories. By comparing radiation and gravitational forces, we also infer some relevant insights into the dynamical evolution of composite grains in the Solar System. We finally explore the possible role of composite fluffy dust grains in igniting an extraterrestrial prebiotic chemistry.