CD40 ligation conditions dendritic cell antigen-presenting function through sustained activation of NF-kappa B

An understanding of the biochemical control of dendritic cell (DC) differentiation/activation is essential for improving T cell immunity by various immunotherapeutic approaches, including DC immunization. Ligation of CD40 enhances DC function, including conditioning for CTL priming. NF-kappaB, and particularly RelB, is an essential control pathway for myeloid DC differentiation. Furthermore, RelB regulates B cell Ag-presenting function. We hypothesized that CD40 ligand (CD40L) and TNF-alpha, which differ in their capacity to condition DC, would also differ in their capacity to activate NF-kappaB. DC differentiated for 2 days from monocytes in the presence of GM-CSF and IL-4 were used as a model, as NF-kappaB activity was constitutively low. The capacity of DC to activate T cells following CD40L treatment was enhanced compared with TNF-alpha treatment, and this was NF-kappaB dependent. Whereas RelB/p50 translocation induced by TNF-alpha was attenuated after 6 h, RelB/p50 nuclear translocation induced by CD40L was sustained for at least 24 h. The mechanism of this difference related to enhanced degradation of IkappaBalpha following CD40L stimulation. However, NF-kappaB activation induced by TNF-alpha could be sustained by blocking autocrine IL-10. These data indicate that NF-kappaB activation is essential for T cell activation by DC, and that this function is enhanced if DC NF-kappaB activation is prolonged. Because IL-10 moderates DC NF-kappaB activation by TNF-alpha, sustained NF-kappaB activation can be achieved by blocking IL-10 in the presence of stimuli that induce TNF-alpha.

Targeting c-Myb expression in human disease

c-Myb is a transcription factor employed in the haematopoietic system and gastrointestinal tract to regulate the exquisite balance between cell division, differentiation and survival. In its absence, these tissues either fail to form, or show aberrant biology. Mice lacking a functional c-myb gene die in utero by day 15 of development. When inappropriately expressed, as is common in leukaemia and epithelial cancers of the breast, colon and gastro-oesophagus, c-Myb appears to activate gene targets of key importance to cancer progression and metastasis. These genes include cyclooxygenase-2 (COX-2), Bcl-2, Bcl-X-L and c-Myc, which influence diverse processes such as angiogenesis, proliferation and apoptosis. The clinical potential for blocking c-Myb expression in malignancies is based upon strong preclinical data and some trial-based evidence. The modest clinical experience to date has been with haematopoietic malignancies, but other disease classes may be amenable to similar interventions. The frontline agents to achieve this are nuclease-resistant oligodeoxynucleotides (ODNs), which are proving to be acceptable therapeutic reagents in terms of tolerable toxicities and delivery. Nevertheless, further effort must be focused on improving their efficacy, eliminating non-specific toxicity and optimising delivery. Optimisation issues aside, it would appear that anti-c-Myb therapies will be used with most success when combined with other agents, some of which will be established cytotoxic and differentiation-inducing drugs. This review will explore the future strategic use of ODNs in vivo, focusing on a wide spectrum of diseases, including several beyond the haematopoietic malignancies, in which c-Myb appears to play a role.

The force-velocity relationship of the human soleus muscle during submaximal voluntary lengthening actions

In experiments on isolated animal muscle, the force produced during active lengthening contractions can be up to twice the isometric force, whereas in human experiments lengthening force shows only modest, if any, increase in force. The presence of synergist and antagonist muscle activation associated with human experiments in situ may partly account for the difference between animal and human studies. Therefore, this study aimed to quantify the force-velocity relationship of the human soleus muscle and assess the likelihood that co-activation of antagonist muscles was responsible for the inhibition of torque during submaximal voluntary plantar flexor efforts. Seven subjects performed submaximal voluntary lengthening, shortening(at angular, velocities of +5, -5, +15, -15 and +30, and -30degrees s(-1)) and isometric plantar flexor efforts against an ankle torque motor. Angle-specific (90degrees) measures of plantar flexor torque plus surface and intramuscular electromyography from soleus, medial gastrocnemius and tibialis anterior were made. The level of activation (30% of maximal voluntary isometric effort) was maintained by providing direct visual feedback of the soleus electromyogram to the subject. In an attempt to isolate the contribution of soleus to the resultant plantar flexion torque, activation of the synergist and antagonist muscles were minimised by: (1) flexing the knee of the test limb, thereby minimising the activation of gastrocnemius, and (2) applying an anaesthetic block to the common peroneal nerve to eliminate activation of the primary antagonist muscle, tibialis anterior and the synergist muscles, peroneus longus and peroneus brevis. Plantar flexion torque decreased significantly (P<0.05) after blocking the common peroneal nerve which was likely due to abolishing activation of the peroneal muscles which are synergists for plantar flexion. When normalised to the corresponding isometric value, the force-velocity relationship between pre- and post-block conditions was not different. In both conditions, plantar flexion torques during shortening actions were significantly less than the isometric torque and decreased at faster velocities. During lengthening actions, however, plantar flexion torques were not significantly different from isometric regardless of angular velocity. It was concluded that the apparent inhibition of lengthening torques during voluntary activation is not due to co-activation of antagonist muscles. Results are presented as mean (SEM).

Measuring the decoherence rate in a semiconductor charge qubit

We describe a method by which the decoherence time of a solid-state qubit may be measured. The qubit is coded in the orbital degree of freedom of a single electron bound to a pair of donor impurities in a semiconductor host. The qubit is manipulated by adiabatically varying an external electric field. We show that by measuring the total probability of a successful qubit rotation as a function of the control field parameters, the decoherence rate may be determined. We estimate various system parameters, including the decoherence rates due to electromagnetic fluctuations and acoustic phonons. We find that, for reasonable physical parameters, the experiment is possible with existing technology. In particular, the use of adiabatic control fields implies that the experiment can be performed with control electronics with a time resolution of tens of nanoseconds.

The pareto-stability concept is a natural solution concept for discrete matching markets with indifferences

In a decentralized setting the game-theoretical predictions are that only strong blockings are allowed to rupture the structure of a matching. This paper argues that, under indifferences, also weak blockings should be considered when these blockings come from the grand coalition. This solution concept requires stability plus Pareto optimality. A characterization of the set of Pareto-stable matchings for the roommate and the marriage models is provided in terms of individually rational matchings whose blocking pairs, if any, are formed with unmatched agents. These matchings always exist and give an economic intuition on how blocking can be done by non-trading agents, so that the transactions need not be undone as agents reach the set of stable matchings. Some properties of the Pareto-stable matchings shared by the Marriage and Roommate models are obtained.

Cranial anatomy of a new genus of hyperodapedontine rhynchosaur (Diapsida, Archosauromorpha) from the Upper Triassic of southern Brazil

Detailed description of the cranial anatomy of the rhynchosaur previously known as Scaphonyx sulcognathus allows its assignment to a new genus Teyumbaita. Two nearly complete skulls and a partial skull have been referred to the taxon, all of which come from the lower part of the Caturrita Formation, Upper Triassic of Rio Grande do Sul, southern Brazil. Cranial autapomorphies of Teyumbaita sulcognathus include anterior margin of nasal concave at midline, prefrontal separated from the ascending process of the maxilla, palatal ramus of pterygoid expanded laterally within palatines, dorsal surface of exoccipital markedly depressed, a single tooth lingually displaced from the main medial tooth-bearing area of the maxilla, and a number of other characters (such as skull broader than long; a protruding orbital anterior margin; anguli oils extending to anterior ramus of the jugal; bar between the orbit and the lower temporal fenestra wider than 0.4 of the total orbital opening; mandibular depth reaching more than 25% of the total length) support its inclusion in Hyperodapedontinae. T. sulcognathus is the only potential Norian rhynchosaur, suggesting that the group survived the end-Carnian extinction event.

Magnetic Investigation of CoFe(2)O(4) Nanoparticles Supported in Biocompatible Polymeric Microsphere

Magnetic investigation of spinel ferrite nanoparticles dispersed in biocompatible polymeric microspheres is reported in this study. X-ray diffraction data analysis confirms the presence of nanosized CoFe(2)O(4) particles (mean size of similar to 8 nm). This finding is corroborated by transmission electron microscopy micrographs. Magnetization isotherms suggest a spin disorder likely occurring at the nanoparticle`s surface. The saturation magnetization value is used to estimate particle concentration of 1.6 x 10(18) cm(-3) dispersed in the polymeric template. A T(1/2) dependence of the coercive field is determined in the low-temperature region (T < 30 K). The model of non-interacting mono-domains is used to estimate an effective magnetic anisotropy of K(eff) = 0.6 x 10(5) J/m(3). The K(eff) value we found is lower than the value reported for spherically-shaped CoFe(2)O(4) nanoparticles, though consistent with the low coercive field observed in the investigated sample.

Intergeneric phylogenetic relationships in catfishes of the Loricariinae (Siluriformes: Loricariidae), with the description of Fonchiiloricaria nanodon: a new genus and species from Peru

Recent investigations in the upper Rio Huallaga in Peru revealed the presence of an intriguing species of the Loricariinae. To characterize and place this species within the evolutionary tree of the subfamily, a molecular phylogeny of this group was inferred based on the 12S and 16S mitochondrial genes and the nuclear gene F-reticulon4. The phylogeny indicated that this distinctive species was a member of the subtribe Loricariina. Given its phylogenetic placement, and its unusual morphology, this species is described as a new genus and new species of Loricariinae: Fonchiiloricaria nanodon. This new taxon is diagnosed by usually possessing one to three premaxillary teeth that are greatly reduced; lips with globular papillae on the surface; the distal margin of lower lip bearing short, triangular filaments; the premaxilla greatly reduced; the abdomen completely covered by plates, with the plates between lateral abdominal plates small and rhombic; a caudal fin with 14 rays; the orbital notch absent; five lateral series of plates; dorsal-fin spinelet absent; preanal plate present, large and solid, and of irregular, polygonal shape, the caudal peduncle becoming more compressed posteriorly for the last seven to 10 plates. (C) 2011 The Authors Journal of Fish Biology (C) 2011 The Fisheries Society of the British Isles

Overshadowing in conditioned taste aversion or in conditioned emotional response after neonatal ventral hippocampal lesions in rats

The neonatal hippocampus lesion thought to model schizophrenia should show the same modifications in behavioural tests as other models, especially pharmacological models. namely decreased latent inhibition, blocking and overshadowing. The present study is set out to evaluate overshadowing in order to complement our previous studies, which had tested latent inhibition. ""Overshadowing"" refers to the decreased conditioning that occurs when the to-be-conditioned stimulus is combined with another stimulus at the conditioning stage. We used the same two Pavlovian conditioning paradigms as in our previous works, namely conditioned taste aversion (CTA) and conditioned emotional response (CER). A sweet taste overshadowed a salty conditioned stimulus, and a tone overshadowed a flashing light. Totally different stimuli were used to counter possible sensory biases. The protocols were validated with two groups of Sprague Dawley rats. The same two protocols were then applied to a cohort of rats whose ventral hippocampus had been destroyed when they were 7 days old. Only rats with extended ventral hippocampus lesions were included. The overall effect of Pavlovian conditioning was attenuated, significantly so in the conditioned emotional response paradigm, but overshadowing appeared not to be modified in either the conditioned emotional response or the conditioned taste aversion paradigm. (C) 2008 Elsevier B.V. All rights reserved.

The role of micro-anchor devices in medial canthopexy

Telecanthus, the lateral displacement of the medial canthus, can be a congenital deformity or can occur after facial trauma or tumor resection. Treatment of telecanthus remains a challenge for plastic surgeons. For proper correction, it is necessary to shift the medial canthus medially, fixing its tendon to the bone. The ideal technique would allow easy, safe, and stable fixation of the tendon, permit a unilateral approach with minimal incisions, and be cost-effective. The purpose of this study was to evaluate the feasibility and results (immediate and long-term) of medial telecanthus repair using ipsilateral titanium microanchor fixation. Nine patients, 7 with unilateral telecanthus and 2 with bilateral telecanthus, underwent ipsilateral canthopexy involving a microanchor device. Anthropometric measurements of the orbital regions were taken before, immediately after, and at 1 year after surgery. Data for the affected sides were compared with those for the unaffected sides, and the evolution of those values was assessed throughout the 1-year follow-up period. For all patients, the final values were lower than those initially obtained. At 1 year after surgery, the intercanthal distance was reduced to age-adjusted normal values in all cases. On the operated side, stable improvement was observed in terms of the distance from the medial canthus to the midline, although some degree of recurrence was noted in most of the patients. The use of a microanchor system for medial canthopexy can be considered an easily performed and effective option for treating canthal dystopia, especially when an ipsilateral approach is preferred.

The Tessier Number 5 Facial Cleft: Surgical Strategies and Outcomes in Six Patients

The Tessier no. 5 facial cleft is an extremely rare congenital malformation. Only 26 cases have been described In the English-language literature. The cleft begins In the upper lip just medial to the oral commissure, extending across the cheek as a groove ending at the junction of the middle and lateral thirds of the lower eyelid. The bone Involvement usually Includes an alveolar cleft in the premolar region, extends across the maxilla lateral to the Infraorbital nerve, up to the infraorbital rim and orbital floor. The goals of the surgical procedure Include reconstructing the lower eyelid, repositioning the lateral canthus, closure of the labiomaxillary cleft, and restoration of the skeletal continuity (including the orbital floor defect) with bone grafts. We present six patients with the Tessier no. 5 facial cleft who have been treated in our combined centers and discuss the surgical options and difficulties faced in the reconstruction of this rare and challenging craniofacial malformation. To date, we have treated six patients (two with bilateral and four with unilateral clefts). Three of the patients with unilateral clefting had an associated no. 4 cleft and one patient with a bilateral cleft had an associated no. 3 cleft. This paper represents the largest series to date documenting surgery for patients with the Tessier no. 5 facial cleft.

Zipping up transcription factors: Rational design of anti-Jun and anti-Fos peptides

Various members of the bZip and bHLH-Zip families of eukaryotic transcription factors, including Jun, Fos, and Myc, have been identified as oncoproteins; mutation or deregulated expression of these proteins leads to certain types of cancer. These proteins can only bind to their cognate DNA enhancer sites following homodimerization, or heterodimerization with another family member, via their leucine zipper domain. Thus, a novel anticancer strategy would be to inhibit dimerization of these proteins, thereby blocking their DNA binding and transactivation functions. In this paper we show that it is possible to rationally design leucine zipper peptides that bind with high affinity to the leucine zipper dimerization domains of c-Jun and c-Fos, thus preventing the formation of functional c-Jun homodimers and c-Jun:c-Fos heterodimers; we refer to such peptides as superzippers (SZs). In vivo, c-Jun:SZ and c-Fos:SZ heterodimers should be nonfunctional as they lack one of the two basic domains that are essential for DNA binding. While the transport of a peptidic agent into cells often poses a severe obstacle to its therapeutic use, we show that a 46-residue leucine zipper peptide can be transported into HeLa cells by coupling it to a 17-residue carrier peptide from the Antennapedia homeodomain, thus paving the way for detailed studies of the therapeutic potential of superzipper peptides.

The Carvedilol`s Beta-Blockade in Heart Failure and Exercise Training`s Sympathetic Blockade in Healthy Athletes during the Rest and Peak Effort

In recent years, beta-blocker therapy has become a primary pharmacologic intervention in patients with heart failure by blocking the sympathetic activity. To compare the exercise training`s sympathetic blockade in healthy subjects (athletes) and the carvedilol`s sympathetic blockade in sedentary heart failure patients by the evaluation of the heart rate dynamic during an exercise test. A total of 26 optimized and 49 nonoptimized heart failure patients in a stable condition (for, at least, 3 months), 15 healthy athletes and 17 sedentary healthy subjects were recruited to perform a cardiopulmonary exercise test. The heart rate dynamic (rest, reserve, peak and the peak heart rate in relation to the maximum predicted for age) was analyzed and compared between the four groups. The heart rate reserve was the same between optimized (48 +/- 15) and nonoptimized (49 +/- 18) heart failure patients (P < 0.0001). The athletes (188 +/- 9) showed a larger heart rate reserve compared to sedentary healthy subjects (92 +/- 10, P < 0.0001). Athletes and healthy sedentary reached the maximum age-predicted heart ratefor their age, but none of the heart failure patients did. The carvedilol`s sympathetic blockade occurred during the rest and during the peak effort in the same proportion, but the exercise training`s sympathetic blockade in healthy subjects occurred mainly in the rest.

Characterization of Superparamagnetic Iron Oxide Coated with Silicone Used as Contrast Agent for Magnetic Resonance Image for the Gastrointestinal Tract

The present work is a report of the characterization of superparamagnetic iron oxide nanoparticles coated with silicone used as a contrast agent in magnetic resonance imaging of the gastrointestinal tract. The hydrodynamic size of the contrast agent is 281.2 rim, where it was determined by transmission electron microscopy and a Fe(3)O(4) crystalline structure was identified by X-ray diffraction, also confirmed by Mossbauer Spectroscopy. The blocking temperature of 190 K was determined from magnetic measurements based on the Zero Field Cooled and Field Cooled methods. The hysteresis loops were measured at different temperatures below and above the blocking temperature. Ferromagnetic resonance analysis indicated the superparamagnetic nature of the nanoparticles and a strong temperature dependence of the peak-to-peak linewidth Delta H(pp), giromagnetic factor g, number of spins N(S) and relaxation time T(2) were observed. This behavior can be attributed to an increase in the superexchange interaction.

Prion protein ablation increases cellular aggregation and embolization contributing to mechanisms of metastasis

Cellular Prion Protein (PrP(C)) is a cell surface protein highly expressed in the nervous system, and to a lesser extent in other tissues. PrP(C) binds to the extracellular matrix laminin and vitronectin, to mediate cell adhesion and differentiation. Herein, we investigate how PrP(C) expression modulates the aggressiveness of transformed cells. Mesenchymal embryonic cells (MEC) from wildtype (Prnp(+/+)) and PrP(C)-null (Prnp(0/0)) mice were immortalized and transformed by co-expression of ras and myc. These cells presented similar growth rates and tumor formation in vivo. When injected in the tail vein, PrnP(0/0)raS/myc cells exhibited increased lung colonization compared with Prnp(+/+)ras/myc cells. Additionally, Prnp(0/0)ras/myc cells form more aggregates with blood components than Prnp(+/+)ras/myc cells, facilitating the arrest of Prnp(0/0)ras/myc cells in the lung vasculature. Integrin alpha(v)beta(3) is more expressed and activated in MEC and in transformed Prnp(0/0) cells than in the respective Prnp(+/+) cells. The blocking of integrin alpha(v)beta(3) by RGD peptide reduces lung colonization in transformed Prnp(0/0) cells to similar levels of those presented by transformed Prnp(+/+) cells. Our data indicate that PrP(C) negatively modulates the expression and activation of integrin alpha(v)beta(3) resulting in a more aggressive phenotype. These results indicate that PrP(C) may have main implications in modulating metastasis formation. (C) 2009 UICC