Detection of a C-insertion polymorphism within the human tumor necrosis factor alpha (TNFA) gene

We have identified a C-insertion polymorphism in the 5'UTR of the first exon of the human tumor necrosis factor alpha (TNFA) gene. TNFA is a cytokine that plays an important role in the inflammatory response.     

Rhizobium leguminosarum exoB mutants are deficient in the synthesis of UDP-glucose 4'-epimerase

Rhizobium leguminosarum bv. viciae Exo- mutant strains RBL5523,exo7::Tn5,RBL5523,exo8::Tn5 and RBL5523,exo52::Tn5 are affected in nodulation and in the syntheses of lipopolysaccharide, capsular polysaccharide, and exocellular polysaccharide. These mutants were complemented for nodulation and for the syntheses of these polysaccharides by plasmid pMP2603. The gene in which these mutants are defective is functionally homologous to the exoB gene of Rhizobium meliloti. The repeating unit of the residual amounts of EPS still made by the exoB mutants of R. leguminosarum bv. viciae lacks galactose and the substituents attached to it. The R. leguminosarum bv. viciae and R. meliloti exoB mutants fail to synthesize active UDP-glucose 4'-epimerase.     

Microhabitat selection in the common lizard: implications of biotic interactions,age, sex,local processes,and model transferability among populations

Modeling species' habitat requirements are crucial to assess impacts of global change, for conservation efforts and to test mechanisms driving species presence. While the influence of abiotic factors has been widely examined, the importance of biotic factors and biotic interactions, and the potential implications of local processes are not well understood. Testing their importance requires additional knowledge and analyses at local habitat scale. Here, we recorded the locations of species presence at the microhabitat scale and measured abiotic and biotic parameters in three different common lizard (Zootoca vivipara) populations using a standardized sampling protocol. Thereafter, space use models and cross‐evaluations among populations were run to infer local processes and estimate the importance of biotic parameters, biotic interactions, sex, and age. Biotic parameters explained more variation than abiotic parameters, and intraspecific interactions significantly predicted the spatial distribution. Significant differences among populations in the relationship between abiotic parameters and lizard distribution, and the greater model transferability within populations than between populations are in line with effects predicted by local adaptation and/or phenotypic plasticity. These results underline the importance of including biotic parameters and biotic interactions in space use models at the population level. There were significant differences in space use between sexes, and between adults and yearlings, the latter showing no association with the measured parameters. Consequently, predictive habitat models at the population level taking into account different sexes and age classes are required to understand a specie's ecological requirements and to allow for precise conservation strategies. Our study therefore stresses that future predictive habitat models at the population level and their transferability should take these parameters into account.     

The preclinical pharmacology of the high affinity anti-IL-6R Nanobody? ALX-0061 supports its clinical development in rheumatoid arthritis

IntroductionThe pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody® with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology.MethodsALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control.ResultsALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration.ConclusionsALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0651-0) contains supplementary material, which is available to authorized users.     

Understanding emerging treatment paradigms in rheumatoid arthritis

Treatment strategies for rheumatoid arthritis (RA) will continue to evolve as new drugs are developed, as new data become available, and as our potential to achieve greater and more consistent outcomes becomes more routine. Many patients will find both symptom relief and modest control of their disease with disease-modifying antirheumatic drugs (DMARDs), yet this course of therapy is clearly not effective in all patients. In fact, despite strong evidence that intensive treatment in the early stages of RA can slow or stop disease progression and may prevent disability, many patients continue to be managed in a stepwise manner and are treated with an ongoing monotherapy regimen with DMARDs. There is now a large body of evidence demonstrating the success of treating RA patients with anti-TNF therapy, usually in combination with methotrexate. As a result of the increased use of anti-TNF therapy, treatment paradigms have changed - and our practice is beginning to reflect this change. In the present review, we summarize the salient points of several recently proposed and emerging treatment paradigms with an emphasis on how these strategies may impact future practice.     

A Dutch Approach to the European Directive on Integrated Pollution Prevention and Control: Using Life-Cycle Assessment for the Integrated Assessment of Technologies

In light of the European Directive on Integrated Pollution Prevention and Control (IPPC Directive), traditional environmental regulation can be improved using the framework of industrial ecology. The objective of the IPPC Directive is to achieve a high level of protection of the environment as a whole (Article 1) by applying the best available techniques (BAT). In essence, the IPPC Directive obliges member states of the European Union to include considerations such as resources, energy, waste, and multimedia emissions when permitting industrial installations. This is a marked contrast to traditional environmental regulation that focuses on individual media of an individual site. In order to take all considerations into account, an integrated assessment of technologies is needed, for which a standard method is currently lacking.
In this article, a systematic approach is introduced for the integrated assessment of IPPC technologies using life-cycle assessment (LCA), a form of environmental assessment that can be broadened to an overall assessment of environmental, economic, and social aspects. This systematic approach has proven to be successful for the environmental assessment of the described cases. It is suggested here that weighting can be omitted for the evaluation of IPPC technologies. Leaving the weighting step to competent authorities of member states and allowing them to consider local issues provides maximum opportunity for the subsidiarity and flexibility principles of the IPPC Directive.