Breakdown of accommodation in nerve: a possible role for persistent sodium current

BACKGROUND: Accommodation and breakdown of accommodation are important elements of information processing in nerve fibers, as they determine how nerve fibers react to natural slowly changing stimuli or electrical stimulation. The aim of the present study was to elucidate the biophysical mechanism of breakdown of accommodation, which at present is unknown. RESULTS: A model of a space-clamped motor nerve fiber was developed. It was found that this new model could reproduce breakdown of accommodation when it included a low-threshold, rapidly activating, persistent sodium current. However, the phenomenon was not reproduced when the persistent sodium current did not have fast activation kinetics or a low activation threshold. CONCLUSION: The present modeling study suggests that persistent, low-threshold, rapidly activating sodium currents have a key role in breakdown of accommodation, and that breakdown of accommodation can be used as a tool for studying persistent sodium current under normal and pathological conditions

Global dynamics of Escherichia coli phosphoproteome in central carbon metabolism under changing culture conditions

Little is known about the role of global phosphorylation events in the control of prokaryote metabolism. By performing a detailed analysis of all protein phosphorylation events previously reported in Escherichia coli, dynamic changes in protein phosphorylation were elucidated under three different culture conditions. Using scheduled reaction monitoring, the phosphorylation ratios of 82 peptides corresponding to 71 proteins were quantified to establish whether serine (S), threonine (T) and tyrosine (Y) phosphorylation events displayed a dynamic profile under changing culture conditions. The ratio of phosphorylation for 23 enzymes from central carbon metabolism was found to be dynamic. The data presented contributes to our understanding of the global role of phosphorylation in bacterial metabolism and highlight that phosphorylation is an important, yet poorly understood, regulatory mechanism of metabolism control in bacteria

Myelin Basic Protein-Induced Production of Tumor Necrosis Factor-α and Interleukin-6, and Presentation of the Immunodominant Peptide MBP85-99 by B Cells from Patients with Relapsing-Remitting Multiple Sclerosis

B cells are involved in driving relapsing-remitting multiple sclerosis (RRMS), as demonstrated by the positive effect of therapeutic B-cell depletion. Aside from producing antibodies, B cells are efficient antigen-presenting and cytokine-secreting cells. Diverse polyclonal stimuli have been used to study cytokine production by B cells, but here we used the physiologically relevant self-antigen myelin basic protein (MBP) to stimulate B cells from untreated patients with RRMS and healthy donors. Moreover, we took advantage of the unique ability of the monoclonal antibody MK16 to recognize the immunodominant peptide MBP85-99 presented on HLA-DR15, and used it as a probe to directly study B-cell presentation of self-antigenic peptide. The proportions of B cells producing TNF-α or IL-6 after stimulation with MBP were higher in RRMS patients than in healthy donors, indicating a pro-inflammatory profile for self-reactive patient B cells. In contrast, polyclonal stimulation with PMA + ionomycin and MBP revealed no difference in cytokine profile between B cells from RRMS patients and healthy donors. Expanded disability status scale (EDSS) as well as multiple sclerosis severity score (MSSS) correlated with reduced ability of B cells to produce IL-10 after stimulation with MBP, indicative of diminished B-cell immune regulatory function in patients with the most severe disease. Moreover, EDSS correlated positively with the frequencies of TNF-α, IL-6 and IL-10 producing B cells after polyclonal stimulation. Patient-derived, IL-10-producing B cells presented MBP85-99 poorly, as did IL-6-producing B cells, particulary in the healthy donor group. B cells from MS patients thus present antigen to T cells in a pro-inflammatory context. These findings contribute to understanding the therapeutic effects of B-cell depletion in human autoimmune diseases, including MS

Orientation-dependent ionization yields from strong-field ionization of fixed-in-space linear and asymmetric top molecules

The yield of strong-field ionization, by a linearly polarized probe pulse, is studied experimentally and theoretically, as a function of the relative orientation between the laser field and the molecule. Experimentally, carbonyl sulfide, benzonitrile and naphthalene molecules are aligned in one or three dimensions before being singly ionized by a 30 fs laser pulse centered at 800 nm. Theoretically, we address the behaviour of these three molecules. We consider the degree of alignment and orientation and model the angular dependence of the total ionization yield by molecular tunneling theory accounting for the Stark shift of the energy level of the ionizing orbital. For naphthalene and benzonitrile the orientational dependence of the ionization yield agrees well with the calculated results, in particular the observation that ionization is maximized when the probe laser is polarized along the most polarizable axis. For OCS the observation of maximum ionization yield when the probe is perpendicular to the internuclear axis contrasts the theoretical results.Comment: 14 pages, 4 figure

OpenFLUX: efficient modelling software for 13C-based metabolic flux analysis

Background: The quantitative analysis of metabolic fluxes, i. e., in vivo activities of intracellular enzymes and pathways, provides key information on biological systems in systems biology and metabolic engineering. It is based on a comprehensive approach combining (i) tracer cultivation on C-13 substrates, (ii) C-13 labelling analysis by mass spectrometry and (iii) mathematical modelling for experimental design, data processing, flux calculation and statistics. Whereas the cultivation and the analytical part is fairly advanced, a lack of appropriate modelling software solutions for all modelling aspects in flux studies is limiting the application of metabolic flux analysis

Spatial temperature distribution in human hairy and glabrous skin after infrared CO2 laser radiation

<p>Abstract</p> <p>Background</p> <p>CO₂lasers have been used for several decades as an experimental non-touching pain stimulator. The laser energy is absorbed by the water content in the most superficial layers of the skin. The deeper located nociceptors are activated by passive conduction of heat from superficial to deeper skin layers.</p> <p>Methods</p> <p>In the current study, a 2D axial finite element model was developed and validated to describe the spatial temperature distribution in the skin after infrared CO₂laser stimulation. The geometry of the model was based on high resolution ultrasound scans. The simulations were compared to the subjective pain intensity ratings from 16 subjects and to the surface skin temperature distributions measured by an infrared camera.</p> <p>Results</p> <p>The stimulations were sensed significantly slower and less intense in glabrous skin than they were in hairy skin (MANOVA, p < 0.001). The model simulations of superficial temperature correlated with the measured skin surface temperature (r > 0.90, <it>p </it>< 0.001). Of the 16 subjects tested; eight subjects reported pricking pain in the hairy skin following a stimulus of 0.6 J/cm²(5 W, 0.12 s, d1/e²= 11.4 mm) only two reported pain to glabrous skin stimulation using the same stimulus intensity. The temperature at the epidermal-dermal junction (depth 50 μm in hairy and depth 133 μm in glabrous skin) was estimated to 46°C for hairy skin stimulation and 39°C for glabrous skin stimulation.</p> <p>Conclusions</p> <p>As compared to previous one dimensional heat distribution models, the current two dimensional model provides new possibilities for detailed studies regarding CO₂laser stimulation intensity, temperature levels and nociceptor activation.</p

RNAi-mediated abrogation of trehalase expression does not affect trehalase activity in sugarcane

To engineer trehalose metabolism in sugarcane (Saccharum spp. hybrids) two transgenes were introduced to the genome: trehalose-6-phosphate synthase- phosphatase (TPSP), to increase trehalose biosynthesis and an RNAi transgene specific for trehalase, to abrogate trehalose catabolism. In RNAi-expressing lines trehalase expression was abrogated in many plants however no decrease in trehalase activity was observed. In TPSP lines trehalase activity was significantly higher. No events of co-integration of TPSP and RNAi transgenes were observed. We suggest trehalase activity is essential to mitigate embryonic lethal effects of trehalose metabolism and discuss the implications for engineering trehalose metabolism