Biological treatment strategies for disc degeneration: potentials and shortcomings

Recent advances in molecular biology, cell biology and material sciences have opened a new emerging field of techniques for the treatment of musculoskeletal disorders. These new treatment modalities aim for biological repair of the affected tissues by introducing cell-based tissue replacements, genetic modifications of resident cells or a combination thereof. So far, these techniques have been successfully applied to various tissues such as bone and cartilage. However, application of these treatment modalities to cure intervertebral disc degeneration is in its very early stages and mostly limited to experimental studies in vitro or in animal studies. We will discuss the potential and possible shortcomings of current approaches to biologically cure disc degeneration by gene therapy or tissue engineering. Despite the increasing number of studies examining the therapeutic potential of biological treatment strategies, a practicable solution to routinely cure disc degeneration might not be available in the near future. However, knowledge gained from these attempts might be applied in a foreseeable future to cure the low back pain that often accompanies disc degeneration and therefore be beneficial for the patien

Interaction of light with a single atom in the strong focusing regime

We consider the near-resonant interaction between a single atom and a focused light mode, where a single atom localized at the focus of a lens can scatter a significant fraction of light. Complementary to previous experiments on extinction and phase shift effects of a single atom, we report here on the measurement of coherently backscattered light. The strength of the observed effect suggests combining strong focusing with the well-established methods of cavity QED. We consider theoretically a nearly concentric cavity, which should allow for a strongly focused optical mode. Simple estimates show that in a such case one can expect a significant single photon Rabi frequency. This opens new perspectives and a possibility to scale up the system consisting of many atom+cavity nodes for quantum networking due to a significant technical simplification of the atom--light interfaces.Comment: 7 pages, 6 figures, followup of workshop "Single photon technologies" in Boulder, CO, 200

Solar flare electron acceleration: comparing theories and observations

A popular scenario for electron acceleration in solar flares is transit-time damping of low-frequency MHD waves excited by reconnection and its outflows. The scenario requires several processes in sequence to yield energetic electrons of the observed large number. Until now there was very little evidence for this scenario, as it is even not clear where the flare energy is released. RHESSI measurements of bremsstrahlung by non-thermal flare electrons yield energy estimates as well as the position where the energy is deposited. Thus quantitative measurements can be put into the frame of the global magnetic field configuration as seen in coronal EUV line observations. We present RHESSI observations combined with TRACE data that suggest primary energy inputs mostly into electron acceleration and to a minor fraction into coronal heating and primary motion. The more sensitive and lower energy X-ray observations by RHESSI have found also small events (C class) at the time of the acceleration of electron beams exciting meter wave Type III bursts. However, not all RHESSI flares involve Type III radio emissions. The association of other decimeter radio emissions, such as narrowband spikes and pulsations, with X-rays is summarized in view of electron accelerationComment: COSPAR meeting Houston 2002, PASP proceedings, in pres

N-glycosylation site occupancy in serum glycoproteins using multiple reaction monitoring liquid chromatography-mass spectrometry

Congenital disorders of glycosylation (CDGs) are a family of N-linked glycosylation defects associated with severe clinical manifestations. In CDG type-I, deficiency of lipid-linked oligosaccharide assembly leads to the underoccupancy of N-glycosylation sites on glycoproteins. Although the level of residual glycosylation activity is known to correlate with the clinical phenotype linked to individual CDG mutations, it is not known whether the degree of N-glycosylation site occupancy by itself correlates with the severity of the disease. To quantify the extent of underglycosylation in healthy control and in CDG samples, we developed a quantitative method of N-glycosylation site occupancy based on multiple reaction monitoring LC-MS/MS. Using isotopically labeled standard peptides, we directly quantified the level of N-glycosylation site occupancy on selected serum proteins. In healthy control samples, we determined 98-100% occupancy for all N-glycosylation sites of transferrin and alpha(1)-antitrypsin. In CDG type-I samples, we observed a reduction in N-glycosylation site occupancy that correlated with the severity of the disease. In addition, we noticed a selective underglycosylation of N-glycosylation sites, indicating preferential glycosylation of acceptor sequons of a given glycoprotein. In transferrin, a preferred occupancy for the first N-glycosylation site was observed, and a decreasing preference for the first, third, and second N-glycosylation sites was observed in alpha(1)-antitrypsin. This multiple reaction monitoring LC-MS/MS method can be extended to multiple glycoproteins, thereby enabling a glycoproteomics survey of N-glycosylation site occupancies in biological samples

Elevated serum biotinidase activity in hepatic glycogen storage disorders-A convenient biomarker

Summary: An elevated serum biotinidase activity in patients with glycogen storage disease (GSD) type Ia has been reported previously. The aim of this work was to investigate the specificity of the phenomenon and thus we expanded the study to other types of hepatic GSDs. Serum biotinidase activity was measured in a total of 68 GSD patients and was compared with that of healthy controls (8.7 ±10; range 7.0-10.6mU/ml; n=6). We found an increased biotinidase activity in patients with GSD Ia (17.7 ±3.9; range: 11.4-24.8; n=21), GSD I non-a (20.9 ±5.6; range 14.6-26.0; n=4), GSD III (12.5 ±-3.6; range 7.8-19.1; n=3), GSD VI (15.4 ±-2.0; range 14.1-17.7; n=) and GSD IX (14.0 ±-3.8; range: 7.5-21.6; n=22). The sensitivity of this test was 100% for patients with GSD Ia, GSD I non-a and GSD VI, 62% for GSD III, and 77% for GSD IX, indicating reduced sensitivity for GSD III and GSD IX, respectively. In addition, we found elevated biotinidase activity in all sera from 5 patients with Fanconi-Bickel Syndrome (15.3 ±-3.7; range 11.0-19.4). Taken together, we propose serum biotinidase as a diagnostic biomarker for hepatic glycogen storage disorder

Deficiency in COG5 causes a moderate form of congenital disorders of glycosylation

The conserved oligomeric Golgi (COG) complex is a tethering factor composed of eight subunits that is involved in the retrograde transport of intra-Golgi components. Deficient biosynthesis of COG subunits leads to alterations of protein trafficking along the secretory pathway and thereby to severe diseases in humans. Since the COG complex affects the localization of several Golgi glycosyltransferase enzymes, COG deficiency also leads to defective protein glycosylation, thereby explaining the classification of COG deficiencies as forms of congenital disorders of glycosylation (CDG). To date, mutations in COG1, COG4, COG7 and COG8 genes have been associated with diseases, which range from severe multi-organ disorders to moderate forms of neurological impairment. In the present study, we describe a new type of COG deficiency related to a splicing mutation in the COG5 gene. Sequence analysis in the patient identified a homozygous intronic substitution (c.1669-15T>C) leading to exon skipping and severely reduced expression of the COG5 protein. This defect was associated with a mild psychomotor retardation with delayed motor and language development. Analysis of different serum glycoproteins revealed a CDG phenotype with typical undersialylation of N- and O-glycans. Retrograde Golgi-to-endoplasmic reticulum trafficking was markedly delayed in the patient's fibroblast upon brefeldin-A treatment, which is a hallmark of COG deficiency. This trafficking delay could be restored to normal values by expressing a wild-type COG5 cDNA in the patient cells. This case demonstrates that COG deficiency and thereby CDG must be taken into consideration even in children presenting mild neurological impairment

On particle acceleration and trapping by Poynting flux dominated flows

Using particle-in-cell (PIC) simulations, we study the evolution of a strongly magnetized plasma slab propagating into a finite density ambient medium. Like previous work, we find that the slab breaks into discrete magnetic pulses. The subsequent evolution is consistent with diamagnetic relativistic pulse acceleration of \cite{liangetal2003}. Unlike previous work, we use the actual electron to proton mass ratio and focus on understanding trapping vs. transmission of the ambient plasma by the pulses and on the particle acceleration spectra. We find that the accelerated electron distribution internal to the slab develops a double-power law. We predict that emission from reflected/trapped external electrons will peak after that of the internal electrons. We also find that the thin discrete pulses trap ambient electrons but allow protons to pass through, resulting in less drag on the pulse than in the case of trapping of both species. Poynting flux dominated scenarios have been proposed as the driver of relativistic outflows and particle acceleration in the most powerful astrophysical jets.Comment: 25 pages, Accepted by Plasma Physics and Controlled Fusio

TeV blazar variability: the firehose instability?

Recently observed minute timescale variability of blazar emission at TeV energies has imposed severe constraints on jet models and TeV emission mechanisms. We focus on a robust jet instability to explain this variability. As a consequence of the bulk outflow of the jet plasma, the pressure is likely to be anisotropic, with the parallel pressure $P_{||}$ in the forward jet direction exceeding the perpendicular pressure $P_{\perp}$. Under these circumstances, the jet is susceptible to the firehose instability, which can cause disruptions in the large scale jet structure and result in variability of the observed radiation. For a realistic range of parameters, we find that the growth timescale of the firehose instability is $\approx$ a few minutes, in good agreement with the observed TeV variability timescales for Mrk 501 (Albert et al. 2007) and PKS 2155-304 (Aharonian et al. 2007).Comment: Accepted for publication, MNRA