The TNFR1 Antagonist Atrosimab Is Therapeutic in Mouse Models of Acute and Chronic Inflammation.

Therapeutics that block tumor necrosis factor (TNF), and thus activation of TNF receptor 1 (TNFR1) and TNFR2, are clinically used to treat inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. However, TNFR1 and TNFR2 work antithetically to balance immune responses involved in inflammatory diseases. In particular, TNFR1 promotes inflammation and tissue degeneration, whereas TNFR2 contributes to immune modulation and tissue regeneration. We, therefore, have developed the monovalent antagonistic anti-TNFR1 antibody derivative Atrosimab to selectively block TNFR1 signaling, while leaving TNFR2 signaling unaffected. Here, we describe that Atrosimab is highly stable at different storage temperatures and demonstrate its therapeutic efficacy in mouse models of acute and chronic inflammation, including experimental arthritis, non-alcoholic steatohepatitis (NASH) and experimental autoimmune encephalomyelitis (EAE). Our data support the hypothesis that it is sufficient to block TNFR1 signaling, while leaving immune modulatory and regenerative responses via TNFR2 intact, to induce therapeutic effects. Collectively, we demonstrate the therapeutic potential of the human TNFR1 antagonist Atrosimab for treatment of chronic inflammatory diseases.

Changes in rainfall distribution promote woody foliage production in the Sahel.

Dryland ecosystems comprise a balance between woody and herbaceous vegetation. Climate change impacts rainfall timing, which may alter the respective contributions of woody and herbaceous plants on the total vegetation production. Here, we apply 30 years of field-measured woody foliage and herbaceous mass from Senegal and document a faster increase in woody foliage mass (+17 kg ha-1 yr-1) as compared to herbaceous mass (+3 kg ha-1 yr-1). Annual rainfall trends were partitioned into core wet-season rains (+0.7 mm yr-1), supporting a weak but periodic (5-year cycles) increase in herbaceous mass, and early/late rains (+2.1 mm yr-1), explaining the strongly increased woody foliage mass. Satellite observations confirm these findings for the majority of the Sahel, with total herbaceous/woody foliage mass increases by 6%/20%. We conclude that the rainfall recovery in the Sahel does not benefit herbaceous vegetation to the same extent as woody vegetation, presumably favoured by increased early/late rains.

"Reduction of tree cover in West African woodlands and promotion in semi-arid farmlands".

Woody vegetation in farmland acts as a carbon sink and provides ecosystem services for local people, but no macro-scale assessments of the impact of management and climate on woody cover exists for drylands. Here we make use of very high spatial resolution satellite imagery to derive wall-to-wall woody cover patterns in tropical West African drylands. Our study reveals a consistently high woody cover in farmlands along all semi-arid and sub-humid rainfall zones (16%), on average only 6% lower than in savannas. In semi-arid Sahel, farmland management increases woody cover to a greater level (12%) than found in neighbouring savannas (6%), whereas farmlands in sub-humid zones have a reduced woody cover (20%) as compared to savannas (30%). In the region as a whole, rainfall, terrain and soil are the most important (80%) determinants of woody cover, while management factors play a smaller (20%) role. We conclude that agricultural expansion cannot generally be claimed to cause woody cover losses, and that observations in Sahel contradict simplistic ideas of a high negative correlation between population density and woody cover.

The missing link: Bordetella petrii is endowed with both the metabolic versatility of environmental bacteria and virulence traits of pathogenic Bordetellae.

BACKGROUND: Bordetella petrii is the only environmental species hitherto found among the otherwise host-restricted and pathogenic members of the genus Bordetella. Phylogenetically, it connects the pathogenic Bordetellae and environmental bacteria of the genera Achromobacter and Alcaligenes, which are opportunistic pathogens. B. petrii strains have been isolated from very different environmental niches, including river sediment, polluted soil, marine sponges and a grass root. Recently, clinical isolates associated with bone degenerative disease or cystic fibrosis have also been described. RESULTS: In this manuscript we present the results of the analysis of the completely annotated genome sequence of the B. petrii strain DSMZ12804. B. petrii has a mosaic genome of 5,287,950 bp harboring numerous mobile genetic elements, including seven large genomic islands. Four of them are highly related to the clc element of Pseudomonas knackmussii B13, which encodes genes involved in the degradation of aromatics. Though being an environmental isolate, the sequenced B. petrii strain also encodes proteins related to virulence factors of the pathogenic Bordetellae, including the filamentous hemagglutinin, which is a major colonization factor of B. pertussis, and the master virulence regulator BvgAS. However, it lacks all known toxins of the pathogenic Bordetellae. CONCLUSION: The genomic analysis suggests that B. petrii represents an evolutionary link between free-living environmental bacteria and the host-restricted obligate pathogenic Bordetellae. Its remarkable metabolic versatility may enable B. petrii to thrive in very different ecological niches.

Molecular monitoring of the intestinal flora by denaturing high performance liquid chromatography.

Gut flora analysis is hampered by the complexity of the intestinal microbiota and by inherent limitations of culture-based approaches. Therefore, culture-independent molecular methods based upon 16S rRNA gene analysis were applied successfully for the analysis of complex microbial communities. However, generally accepted and validated profiling methods such as denaturing and temperature gradient gel electrophoresis (DGGE/TGGE) are still laborious and time consuming. Thus, we adapted the separation of amplified bacterial 16S rRNA gene fragments by denaturing high performance liquid chromatography (DHPLC) using the WAVE Microbial Analysis System as a rapid and convenient means to display complex intestinal bacterial communities and to monitor changes in the gut flora. The separation of 16S rRNA gene fragments amplified from reference strains representing main gut bacterial populations and from human stool samples revealed that DHPLC analysis effectively detects bacterial groups predominant in the human gut flora. The investigation of faecal samples from hospitalized patients before, during and after antibiotic therapy showed that PCR-based DHPLC can be used to monitor gut flora changes. Results from DHPLC analysis were comparable with DGGE profiles generated from the same samples, demonstrating that the adapted DHPLC protocol is well suited for the analysis of complex microbial communities.

Use of denaturing high-performance liquid chromatography for rapid detection and identification of seven Candida species.

A novel denaturing high-performance liquid chromatography (DHPLC)-based technique allows rapid high-resolution analysis of PCR products. We used this technique for unequivocal molecular identification of seven Candida species. We show the application of this PCR/DHPLC approach for direct detection and identification of yeast species from blood cultures and for detection of Candida colonization in the gastrointestinal tract of allogeneic transplant patients.