Search

L-selectin, a lectin-like receptor on all leukocyte classes, functions in adhesive and signaling roles in the recruitment of myeloid cells from the blood to sites of inflammation. Here, we consider L-selectin as a determinant of neurological recovery in a murine model of spinal cord injury (SCI). Spinal cord-injured, L-selectin knock-out (KO) mice (male) showed improved long-term recovery with greater white matter sparing relative to wild-type (WT) mice and reduced oxidative stress in the injured cord at 72 h post-SCI. There was a partial and transient reduction in accumulation of neutrophils in the injured spinal cords of KOs at 24 h post-injury. To complement these findings with KO mice, we sought a pharmacologic means for lowering L-selectin levels. We found that diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), induced the shedding of L-selectin from the cell surface of myeloid subsets, specifically neutrophils and non-classical monocytes, in the blood and the injured spinal cord. Diclofenac administration to injured WT mice enhanced neurological recovery to a level comparable to that of KOs but did not improve recovery in KOs. While diclofenac treatment had no effect on myeloid cell accumulation, there was a reduction in oxidative stress at 72 h post-SCI. These findings implicate L-selectin in secondary pathogenesis beyond a role in leukocyte recruitment and raise the possibility of repurposing diclofenac for the treatment of SCI.

Different forms of procarboxypeptidases (PCPs) zymogens are observed experimentally to show different rates and modes of activation: PCPA1 shows a slow, biphasic, activation pathway compared to PCPA2 and PCPB which have a faster, monotonic activation behavior. Detailed mechanisms involved in activating these zymogen forms to the active enzymes are not well understood yet. In this work, three PCP zymogens (subtypes A1, A2 and B) were in silico converted into the primary cleavage state of zymogens using available X-ray structures. Based on these cleaved forms of zymogen, we are able to investigate their spontaneous dissociation process of the prosegment from its associated enzyme domain using steered molecular dynamics simulation. The simulations revealed the highest rupture force in PCPB followed by PCPA2 and PCPA1. We also found that the cleavage substantially destabilizes most of the hydrogen bonds at the prosegment-enzyme interface in each zymogen structure. The mechanisms of the prosegment unbinding seem to be similar in both PCPA1 and PCPB but different in PCPA2: PCPA1 and PCPB show first rupture in the connecting segment followed by the globular domain, while PCPA2 conversely shows first rupture in the globular domain and then in the connecting segment. Our simulations have included the dynamic and long range conformational effects taking place after the first proteolytic cleavage in PCPs, providing first insights into the activation of carboxypeptidase A1, A2 and B., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Analysis of sedimentation velocity data for indefinite self-associating systems is often achieved by fitting of weight average sedimentation coefficients (s(20,w)) However, this method discriminates poorly between alternative models of association and is biased by the presence of inactive monomers and irreversible aggregates. Therefore, a more robust method for extracting the binding constants for indefinite self-associating systems has been developed. This approach utilizes a set of fitting routines (SedAnal) that perform global non-linear least squares fits of up to 10 sedimentation velocity experiments, corresponding to different loading concentrations, by a combination of finite element simulations and a fitting algorithm that uses a simplex convergence routine to search parameter space. Indefinite self-association is analyzed with the software program isodesfitter, which incorporates user provided functions for sedimentation coefficients as a function of the degree of polymerization for spherical, linear and helical polymer models. The computer program hydro was used to generate the sedimentation coefficient values for the linear and helical polymer assembly mechanisms. Since this curve fitting method directly fits the shape of the sedimenting boundary, it is in principle very sensitive to alternative models and the presence of species not participating in the reaction. This approach is compared with traditional fitting of weight average data and applied to the initial stages of Mg(2+)-induced tubulin self-associating into small curved polymers, and vinblastine-induced tubulin spiral formation. The appropriate use and limitations of the methods are discussed.

Background: Pica is an eating disorder characterized by the irrepressible and elective craving for food and non-food substances. Pagophagia is a particular form characterized by an ingestion of ice, often associated with iron deficiency. We report a case of intense and prolonged pagophagia. We also analyse literature about the nature of the link between pica and iron deficiency., Case Report: A forty-two year old woman was admitted for severe anaemia secondary to iron deficiency possibly related to chronic gynaecological bleeding. A diet investigation revealed a pagophagia of about eighty ice cubes per day developing over five years. Iron supplement corrected the anaemia and the pagophagia disappeared in less than fifteen days without recurrence in the following year., Conclusion: The disappearance of pagophagia after the correction of iron deficiency supports the theory that pagophagia could well be a symptom of iron deficiency.

Objectives: To ascertain the attitude of hospital physicians in the Paris area concerning pica and its relation to iron deficiency and to compare findings with data in the literature., Methods: An anonymous questionnaire was sent to 174 department heads of specialty units caring for iron deficiency patients: internal medicine (n = 56), hepatogastroenterology (n = 39), hematology (n = 13), gynecology and obstetrics (n = 34), pediatrics (n = 32)., Results: The overall response rate was 40.2%. Ninety-seven percent of all the physicians found pica in less than 10% of patients with iron deficiency, and 95.6% considered geophagia as the most frequent pica. For 58.5% of the adult medicine practitioners, pica was regarded only as a cause of iron deficiency, but for 64.7% of the pediatricians, pica was both a cause and a symptom of iron deficiency was not sought in a systemic way in 88.6% of the physicians when a cause of iron deficiency was known., Conclusion: In the majority of the cases, the attitude of hospital physicians concerning pica is in disagreement with published data, suggesting either epidemiological characteristics specific to the Paris area, or unawareness of the phenomenon.

Conventional kinesin is a processive, microtubule-based motor protein that drives movements of membranous organelles in neurons. Amino acid Thr(291) of Drosophila kinesin heavy chain is identical in all superfamily members and is located in alpha-helix 5 on the microtubule-binding surface of the catalytic motor domain. Substitution of methionine at Thr(291) results in complete loss of function in vivo. In vitro, the T291M mutation disrupts the ATPase cross-bridge cycle of a kinesin motor/neck construct, K401-4 (Brendza, K. M., Rose, D. J., Gilbert, S. P., and Saxton, W. M. (1999) J. Biol. Chem. 274, 31506-31514). The pre-steady-state kinetic analysis presented here shows that ATP binding is weakened significantly, and the rate of ATP hydrolysis is increased. The mutant motor also fails to distinguish ATP from ADP, suggesting that the contacts important for sensing the gamma-phosphate have been altered. The results indicate that there is a signaling defect between the motor domains of the T291M dimer. The ATPase cycles of the two motor domains appear to become kinetically uncoupled, causing them to work more independently rather than in the strict, coordinated fashion that is typical of kinesin.

In these studies a constant ERG response was used as a measure of visual sensitivity to different wavelengths of light. The dark-adapted compound eye of Tenodera sinensis is dominated by a single class of photoreceptors. with a major peak of sensitivity at about 510-520 nm, and with a minor peak of sensitivity in the near-ultraviolet region at about 370 nm. The dark-adapted dorsal ocellus does not contain a homogeneous population of sensory receptors. The sensitivity function of the dark-adapted ocellus to longer wavelength light (yellow and red) is determined by a single receptor with a major peak of sensitivity in the green at 510-520 nm with some sensitivity in the near-ultraviolet. Sensitivity at shorter wavelengths (near-ultraviolet and blue), however, involves the stimulation of both this and a near-ultraviolet-sensitive receptor with a maximum sensitivity at about 370 nm. Anatomically, the sensory cells of the dorsal ocellus of Tenodera were determined histologically to be grouped into two distinct regions, each group making its own separate contribution to the ocellar nerve. This may represent the separation of two different photoreceptor types in the ocellus of the mantis.