579 research outputs found
Intra-Articular Fms-Like Tyrosine Kinase 3 Ligand Expression Is a Driving Force in Induction and Progression of Arthritis
Background: One of the hallmarks of rheumatoid arthritis (RA) is hyperplasia and inflammation of the synovial tissue being characterized by in situ occurrence of highly differentiated leukocytes. Fms-like tyrosine kinase 3 (Flt3) has a crucial role in hematopoiesis, regulation of cell proliferation, differentiation and apoptosis. Typically, Flt3 is expressed on early myeloid and lymphoid progenitors and is activated by its soluble ligand (Flt3-L). The highly differentiated cellular pattern in the synovium of the RA patients made us hypothesize that Flt3-L, with its ability to induce proliferation and differentiation, could be of importance in induction and/or progression of arthritis.
Methodology/Principal Findings: To investigate occurrence of Flt3-L in RA we have measured its levels in matched serum and synovial fluid samples from 130 patients and 107 controls. To analyse the pro-inflammatory role of Flt3-L, we continuously overexpressed this protein locally in healthy mouse joints using homologous B-cell line transfected with Flt3-L gene. Additionally, recombinant Flt3-L was instillated intra-articularly in combination with peptidoglycans, a Toll Like Receptor 2-ligand with stong arthritogenic properties. Our results show significantly higher levels of Flt3-L in the synovial fluid as compared to serum levels in RA subjects (p = 0.0001). In addition, RA synovial fluid levels of Flt-3-L were significantly higher than these obtained from synovial fluids originating from non-inflammatory joint diseases (p = 0.022). Intra-articular administration of B-cell line transfected with Flt3-L gene resulted in highly erosive arthritis while inoculation of the same B-cell line without hyperexpression of Flt3-L did not induce erosivity and only in a minority of cases caused synovial proliferation! Flt3-ligand potentiated peptidoglycan induced arthritis as compared to mice injected with peptidoglycan alone (p<0.05).
Conclusions/Significance: Our findings indicate that Flt3-L is strongly expressed at the site of inflammation in human RA. It exerts both pro-inflammatory and tissue destructive properties once in the joint cavity. Owing to these properties, treatment attempts to neutralize this molecule should be considered in RA
Correlated patterns in non-monotonic graded-response perceptrons
The optimal capacity of graded-response perceptrons storing biased and
spatially correlated patterns with non-monotonic input-output relations is
studied. It is shown that only the structure of the output patterns is
important for the overall performance of the perceptrons.Comment: 4 pages, 4 figure
A toy model of the five-dimensional universe with the cosmological constant
A value of the cosmological constant in a toy model of the five-dimensional
universe is calculated in such a manner that it remains in agreement with both
astronomical observations and the quantum field theory concerning the
zero-point fluctuations of the vacuum. The (negative) cosmological constant is
equal to the inverse of the Planck length squared, which means that in the toy
model the vanishing of the observed value of the cosmological constant is a
consequence of the existence of an energy cutoff exactly at the level of the
Planck scale. In turn, a model for both a virtual and a real
particle-antiparticle pair is proposed which describes properly some energetic
properties of both the vacuum fluctuations and created particles, as well as it
allows one to calculate the discrete "bare" values of an elementary-particle
mass, electric charge and intrinsic angular momentum (spin) at the energy
cutoff. The relationships between the discussed model and some phenomena such
as the Zitterbewegung and the Unruh-Davies effect are briefly analyzed, too.
The proposed model also allows one to derive the Lorentz transformation and the
Maxwell equations while considering the properties of the vacuum filled with
the sea of virtual particles and their antiparticles. Finally, the existence of
a finite value of the vacuum-energy density resulting from the toy model leads
us to the formulation of dimensionless Einstein field equations which can be
derived from the Lagrangian with a dimensionless (naively renormalized)
coupling constant.Comment: 52 pages, 1 figure; a post-final, rewritten version with a number of
new remarks and conclusion
Generalizing with perceptrons in case of structured phase- and pattern-spaces
We investigate the influence of different kinds of structure on the learning
behaviour of a perceptron performing a classification task defined by a teacher
rule. The underlying pattern distribution is permitted to have spatial
correlations. The prior distribution for the teacher coupling vectors itself is
assumed to be nonuniform. Thus classification tasks of quite different
difficulty are included. As learning algorithms we discuss Hebbian learning,
Gibbs learning, and Bayesian learning with different priors, using methods from
statistics and the replica formalism. We find that the Hebb rule is quite
sensitive to the structure of the actual learning problem, failing
asymptotically in most cases. Contrarily, the behaviour of the more
sophisticated methods of Gibbs and Bayes learning is influenced by the spatial
correlations only in an intermediate regime of , where
specifies the size of the training set. Concerning the Bayesian case we show,
how enhanced prior knowledge improves the performance.Comment: LaTeX, 32 pages with eps-figs, accepted by J Phys
Milestones and Impact Factors
Environmental Health has just received its first Impact Factor by Thomson ISI. At a level of 2.48, this achievement is quite satisfactory and places Environmental Health in the top 25% of environmental science journals. When the journal was launched in 2002, it was still unclear whether the Open Access publishing model could be made into a viable commercial enterprise within the biomedical field. During the past eight years, Open Access journals have become widely available, although still covering only about 15% of journal titles. Major funding agencies and institutions, including prominent US universities, now require that researchers publish in Open Access journals. Because of the profound role of scientific journals for the sharing of results and communication between researchers, the advent of Open Access may be of as much significance as the transition from handwriting to printing via moveable type. As Environmental Health is an electronic Open Access journal, the numbers of downloads at the journal website can be retrieved. The top-20 list of articles most frequently accessed shows that all of them have been downloaded over 10,000 times. Back in 2002, the first article published was accessed only 49 times during the following month. A year later, the server had over 1,000 downloads per month, and now the total number of monthly downloads approaches 50,000. These statistics complement the Impact Factor and confirm the viability of Open Access in our field of research. The advent of digital media and its decentralized mode of distribution - the internet - have dramatically changed the control and financing of scientific information dissemination, while facilitating peer review, accelerating editorial handling, and supporting much needed transparency. Both the meaning and means of "having an impact" are therefore changing, as will the degree and way in which scientific journals remain "factors" in that impact
Strigolactones inhibit auxin feedback on PIN-dependent auxin transport canalization
Directional transport of the phytohormone auxin is a versatile, plant-specific mechanism regulating many aspects of plant development. The recently identified plant hormones, strigolactones (SLs), are implicated in many plant traits; among others, they modify the phenotypic output of PIN-FORMED (PIN) auxin transporters for fine-tuning of growth and developmental responses. Here, we show in pea and Arabidopsis that SLs target processes dependent on the canalization of auxin flow, which involves auxin feedback on PIN subcellular distribution. D14 receptor- and MAX2 F-box-mediated SL signaling inhibits the formation of auxin-conducting channels after wounding or from artificial auxin sources, during vasculature de novo formation and regeneration. At the cellular level, SLs interfere with auxin effects on PIN polar targeting, constitutive PIN trafficking as well as clathrin-mediated endocytosis. Our results identify a non-transcriptional mechanism of SL action, uncoupling auxin feedback on PIN polarity and trafficking, thereby regulating vascular tissue formation and regeneration
Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden.
Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology
Activating Killer Immunoglobulin Receptors and HLA-C: A successful combination providing HIV-1 control
Several studies demonstrated a relevant role of polymorphisms located within the HLA-B and -C loci and the Killer Immunoglobulin Receptors (KIRs) 3DL1 and 3DS1 in controlling HIV-1 replication. KIRs are regulatory receptors expressed at the surface of NK and CD8+ T-cells that specifically bind HLA-A and -B alleles belonging to the Bw4 supratype and all the -C alleles expressing the C1 or C2 supratype. We here disclose a novel signature associated with the Elite Controller but not with the long-term nonprogressor status concerning 2DS activating KIRs and HLA-C2 alleles insensitive to miRNA148a regulation. Overall, our findings support a crucial role of NK cells in the control of HIV-1 viremia
National support to public health research: a survey of European ministries
Background:
Within SPHERE (Strengthening Public Health Research in Europe), a collaborative study funded by the European Commission, we have assessed the support for public health research at ministry level in European countries.
Methods:
We surveyed the health and science ministries in 25 EU countries and 3 EEA countries, using a broad definition of public-health research at population level. We made over 600 phone calls and emails to identify respondents and to gain answers. We gained formal replies from 42 out of 56 ministries (73% response) in 25 countries. There were 22 completed questionnaires (from 25 ministries), 6 short answers and 11 contacts declaring that their ministries were not responsible for public health research, while in 14 ministries (both ministries in three countries) no suitable ministry contact could be found.
Results:
In most European countries, ministries of health, or their devolved agencies, were regarded as the leading organizations. Most ministries were able to specify thematic areas for public-health research (from three to thirty), and others ministries referred to policy documents, health plans or public-health plans to define research priorities. Ministries and their agencies led on decisions for financial support of public-health research, with less involvement of other external organisations compared with the process of identifying priorities. However, the actual funds available for public health were not easily identifiable. Most ministries relied on general academic means for dissemination of results of public-health research, while ministries get information on the use of public-health research usually through informal means. Ministries made suggestions for strengthening public-health research through initiatives of their own countries and of the European Union: as well as more resources, improving coordination was most frequently suggested.
Conclusion:
There is no common approach to support for public-health research across Europe, and significant gaps in organisation and funding. Health ministries and national agencies value exchange between researchers and policy-makers, civil society organizations, and academic and public authorities, and the application of public-health research results. There would be benefits from better processes of priority setting and improved coordination for research, at regional, national and European levels
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