Authors:Laura von Brzezinski, Paula Säring, Peter Landgraf, Clemens Cammann, Ulrike Seifert, and Daniela C. Dieterich
Application of the proteasome inhibitor Bortezomib for the treatment of haematopoietic malignancies such as multiple myeloma significantly improves the average overall survival of patients. However, one of the most severe side effects is the development of peripheral neuropathies caused by neurotoxic effects of Bortezomib limiting its therapeutic efficacy. With ONX-0914 a specific inhibitor of the β5i (LMP7)-immunosubunit containing proteasomes was developed that targets exclusively the proteasome subtypes mainly expressed in immune cells including B lymphocytes as the origin of multiple myeloma. Furthermore, immunosubunitspecific inhibitors have been shown to be promising tools for the therapy of autoimmune disorders. In the presented study, we analysed the concentration-dependent impact of both inhibitors on primary neurons regarding survival rate, morphological changes, and overall viability. Our results clearly demonstrate that ONX-0914, compared to Bortezomib, is less neurotoxic suggesting its potential as a putative antineoplastic drug and as a candidate for the treatment of autoimmune disorders affecting the peripheral and/or central nervous system.
Authors:Ali Konaté, René Dembélé, Assèta Kagambèga, Issiaka Soulama, Wendpoulomdé A. D. Kaboré, Emmanuel Sampo, Haoua Cissé, Antoine Sanou, Samuel Serme, Soumanaba Zongo, Cheikna Zongo, Alio Mahamadou Fody, Nathalie K. Guessennd, Alfred S. Traoré, Amy Gassama-Sow, and Nicolas Barro
Diarrheagenic Escherichia coli (DEC) is important bacteria of children’s endemic and epidemic diarrhea worldwide. The aim of this study was to determine the prevalence of DEC isolated from stool samples collected from children with acute diarrhea living in Ouagadougou, Burkina Faso. From August 2013 to October 2015, stool samples were collected from 315 children under 5 years of age suffering from diarrhea in the “Centre Médical avec Antenne Chirurgicale (CMA)” Paul VI and the CMA of Schiphra. E. coli were isolated and identified by standard microbiological methods, and the 16-plex PCR method was used to further characterize them. Four hundred and nineteen (419) E. coli strains were characterized, of which 31 (7.4%) DEC pathotypes were identified and classified in five E. coli pathotypes: 15 enteroaggregative E. coli (EAEC) (48.4%), 8 enteropathogenic E. coli (EPEC) (25.8%) with 4 typical EPEC and 4 atypical EPEC, 4 enteroinvasive E. coli (EIEC) (12.9%), 3 enterohemorrhagic E. coli (EHEC) 9.67%, and 1 enterotoxigenic E. coli (ETEC) 3.2%. The use of multiplex PCR as a routine in clinical laboratory for the detection of DEC would be a useful mean for a rapid management of an acute diarrhea in children.
Authors:Eliane von Klitzing, Stefan Bereswill, and Markus M. Heimesaat
The World Health Organization has rated multidrug-resistant (MDR) Pseudomonas aeruginosa as a critical threat to human health. In the present study, we performed a survey of intestinal colonization, and local and systemic immune responses following peroral association of secondary abiotic mice with either a clinical MDR P. aeruginosa or a commensal murine Escherichia coli isolate. Depletion of the intestinal microbiota following antibiotic treatment facilitated stable intestinal colonization of both P. aeruginosa and E. coli that were neither associated with relevant clinical nor histopathological sequelae. Either stable bacterial colonization, however, resulted in distinct innate and adaptive immune cell responses in the intestines, whereas a pronounced increase in macrophages and monocytes could be observed in the small as well as large intestines upon P. aeruginosa challenge only, which also applied to colonic T lymphocytes. In addition, TNF secretion was exclusively elevated in large intestines of P. aeruginosa-colonized mice. Strikingly, association of secondary abiotic mice with MDR P. aeruginosa, but not commensal E. coli, resulted in pronounced systemic pro-inflammatory responses, whereas anti-inflammatory responses were dampened. Hence, intestinal carriage of MDR P. aeruginosa as compared to a mere commensal Gram-negative strain in otherwise healthy individuals results in distinct local and systemic pro-inflammatory sequelae.
Authors:Anne Grunau, Ulrike Escher, Stefan Bereswill, and Markus M. Heimesaat
The rising incidences of infections with multidrug-resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa (PA) have gained increasing attention in medicine, but also in the general public and global health politics. The mechanisms underlying opportunistic pathogen—host interactions are unclear, however. To address this, we challenged secondary abiotic IL10−/− mice deficient for Toll-like receptor-4 (TLR4−/− × IL10−/−), the main receptor of the Gram-negative cell wall constituent lipopolysaccharide, with a clinical MDR PA isolate. Despite higher intestinal colonization densities, apoptotic colonic epithelial cell numbers were lower in TLR4−/− × IL10−/− mice as compared to IL10−/− controls at day 14 postinfection (p.i.), whereas proliferating/regenerating cells had increased in the latter only. Furthermore, PA-colonized TLR4−/− × IL10−/− mice displayed less distinct innate and adaptive immune cell responses in the colon as compared to IL10−/− counterparts that were accompanied by lower nitric oxide concentrations in mesenteric lymph nodes in the former at day 14 p.i. Conversely, splenic NO levels were higher in both naive and PA-colonized TLR4-deficient IL10−/− mice versus IL10−/− controls. Remarkably, intestinal MDR PA was able to translocate to extra-intestinal including systemic compartments of TLR4−/− × IL10−/− mice only. Hence, MDR PA-induced intestinal and systemic immune responses observed in secondary abiotic IL10−/− mice are TLR4-dependent.
Climate change brings along trend-like changes as well as changes in the temporal variations in environmental conditions which interact with the biological dynamics of ecological systems. Therefore, only studies covering several decades may unveil long term trends in ecological systems, such as in animal communities. To demonstrate if recent climatic changes have caused fundamental changes in the structure of a key arthropod community, I studied the long-term dynamics of ant colonies for 37 years on a sandy grassland in central Hungary. To be able to monitor colonies – the natural units of ant communities – with the possible least disturbance, I applied two grids of a total of 80 slate plates as artificial nesting sites. Prior to the presented study, a well-defined spatial ant community structure had been identified in the studied habitat, which consisted of three species groups (dune top, transitional and dune slack groups), occupying different habitat patches. During the study period 2813 nests of 11 ant species were recorded under the slates. Over the 37 years, community pattern markedly changed, dune slack species disappeared from the studied plots, while the frequency of drought-tolerant dune top species increased by a significant trend. No significant trend was observed in the case of the transitional species group. On the species population level, two species, Lasius niger and Formica cunicularia, showed an intensive population decline; while the Plagiolepis taurica population significantly increased and spatially joined the transitional species group in the dune slack in the second half of the project. These changes led to a major decline in species richness and a homogenization of species composition across habitat patches. Multiple correlation analyses revealed that the depletion of groundwater had the strongest relationship with these population trends. The study indicates that climate change can be linked to a fundamental change in the community structure of major ecosystem actors.
Authors:D. S. G. Henriques, P. A. V. Borges, and R. Gabriel
How are bryophyte alpha and beta diversities distributed across spatial scales along an elevational gradient in an oceanic island? Which mechanisms and drivers operate to shape them? Starting from a multiscale hierarchical sampling approach along an 1000 m elevational transect, we used additive diversity partitioning and null modeling to evaluate the contributions of the alpha and beta diversity components to overall bryophyte diversity in Terceira Island, Azores. Substrate-level diversity patterns were explored by means of the Sørensen Similarity Index and the Lloyd Index of Patchiness. Elevation-level beta diversity was decomposed into its replacement and richness differences components, with several environmental variables being evaluated as diversity predictors. Bryophyte diversity proved to be primarily due to beta diversity between elevation sites, followed by diversity among substrates. Compositional differences between neighboring sites decreased with elevation, being mainly caused by species replacement and correlating with differences in relative humidity and disturbance. At the substrate level, we found a great homogeneity in terms of species composition, coupled with a low substrate specialization rate. We conclude that, in Terceira’s native vegetation patches, regional processes, such as environmental gradients associated with elevation, play a greater role in shaping bryophyte diversity than local processes. Moister and less disturbed areas at mid-high elevation harbor a richer bryoflora, consistently more similar and stable between neighbouring sites. Simultaneously, the different substrates available are somewhat ecologically redundant, supporting few specialized species, pointing to these areas providing optimal habitat conditions for bryophytes. Our findings provide a better understanding of how bryophyte diversity is generated in Terceira Island, indicating that management and conservation measures should focus on island-level approaches, aiming to protect and rehabilitate additional natural vegetation patches at different elevations, especially in the severely disturbed lowlands.
Authors:D. Qi, X. Wieneke, X. Zhou, X. Jiang, and P. Xue
Karst rocky desertification (KRD) is a process of soil desertification, which leads to the decline of soil quality and biomass. We conducted a plant community survey in KRD areas in Chongqing, China. Our aims were to determine key soil properties that shape plant communities and to identify essential leaf functional traits (LFTs) in responding to the progression of KRD. The vegetation survey was carried in a total of twenty study sites (five replicates for four stages of KRD) in the Wushan County in Chongqing, China. Leaves were collected from all the species in every site and measured/calculated for five LFTs, namely, specific leaf area, leaf area, leaf thickness, leaf tissue density, and leaf dry matter content. Soil samples were collected in triplicates in each site to measure soil properties. We found that the overall richness and diversity of community decreased along with the progression of KRD. Phanerophytes predominated in all the KRD areas. Soil pH was the main determinant of vegetation structure. Leaves with lower area yet higher density had the optimal adaptability in KRD regions, which can be planted as pioneer vegetation to restore land in KRD regions.
Authors:Julia Münch, Ralf Matthias Hagen, Martin Müller, Viktor Kellert, Dorothea Franziska Wiemer, Rebecca Hinz, Norbert Georg Schwarz, and Hagen Frickmann
The effectiveness of a disinfectant-based decolonization strategy for multidrug-resistant bacteria like extended spectrum β-lactamase (ESBL)-positive Gram-negative bacteria with or without additional fluoroquinolon and carbapenem resistance as well as vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus was assessed.
Between 2011 and 2015, 25 patients from Libya, Syria, and the Ukraine with war traumata were treated at the Bundeswehr hospital Hamburg. The patients were heavily colonized and infected with multidrug-resistant bacteria, altogether comprising 371 distinct combinations of pathogens and isolation sites. Local disinfection was assessed for effectiveness regarding successful decolonization of multidrug-resistant bacteria.
Altogether, 170 cases of successful decolonization were observed, comprising 95 (55.8%) such events at sampling sites that were accessible to disinfecting procedures. The remaining 75 (44.2%) decolonization events had to be considered as spontaneous. In contrast, 95 out of 172 (55.2%) colonized isolation sites that were accessible to disinfection procedures were successfully decolonized. Patient compliance with the enforced hygiene procedures was associated with decolonization success. Systemic antibiotic therapy did not relevantly affect isolation time.
Disinfecting washing moderately supports local decolonization of multidrug-resistant pathogens in comparison with spontaneous decolonization rates if the patients’ compliance with the applied hygiene procedures is ensured.
Authors:Olugbenga A. Olowe, Olufunmilola B. Makanjuola, Adeniyi S. Adekanmi, Olusola J. Adefioye, and Rita A. Olowe
Tuberculosis (TB) is the second leading cause of death from infectious disease globally with its impact more dramatic in resource limited settings. Individuals with human immunodeficiency virus (HIV) infection who also develop tuberculosis represent a significant challenge to TB control. This study was carried out to determine the prevalence of TB—HIV coinfection and pattern of infection among TB patients. We also compared treatment outcome among coinfected patients with those not coinfected.
A six-year retrospective review of records of patients managed at the Tuberculosis Treatment Center of the LAUTECH Teaching Hospital, South-Western Nigeria from January 2009 to December 2014 was carried out.
One hundred and five (26.3%) of the 399 TB patients seen in the study period were coinfected with HIV. About 10% of the subjects had extrapulmonary tuberculosis. Treatment failure was significantly worse among patients who had both HIV and TB compared with those who had TB only (49.5% vs. 32%, p = 0.001). Death rate was also higher in the coinfected individuals implying a poorer clinical outcome.
High prevalence of TB—HIV coinfection and poor treatment outcome in this group of individuals, though predictable, calls for a more concerted effort in the management of TB—HIV coinfection.
Authors:Jana Niemz, Stefanie Kliche, Marina C. Pils, Eliot Morrison, Annika Manns, Christian Freund, Jill R. Crittenden, Ann M. Graybiel, Melanie Galla, Lothar Jänsch, and Jochen Huehn
Using quantitative phosphopeptide sequencing of unstimulated versus stimulated primary murine Foxp3+ regulatory and Foxp3− conventional T cells (Tregs and Tconv, respectively), we detected a novel and differentially regulated tyrosine phosphorylation site within the C1 domain of the guanine-nucleotide exchange factor CalDAG GEFI. We hypothesized that the Treg-specific and activation-dependent reduced phosphorylation at Y523 allows binding of CalDAG GEFI to diacylglycerol, thereby impacting the formation of a Treg-specific immunological synapse. However, diacylglycerol binding assays of phosphomutant C1 domains of CalDAG GEFI could not confirm this hypothesis. Moreover, CalDAG GEFI−/− mice displayed normal Treg numbers in thymus and secondary lymphoid organs, and CalDAG GEFI−/− Tregs showed unaltered in vitro suppressive capacity when compared to CalDAG GEFI+/+ Tregs. Interestingly, when tested in vivo, CalDAG GEFI−/− Tregs displayed a slightly reduced suppressive ability in the transfer colitis model when compared to CalDAG GEFI+/+ Tregs. Additionally, CRISPR-Cas9-generated CalDAG GEFI−/− Jurkat T cell clones showed reduced adhesion to ICAM-1 and fibronectin when compared to CalDAG GEFI-competent Jurkat T cells. Therefore, we speculate that deficiency in CalDAG GEFI impairs adherence of Tregs to antigen-presenting cells, thereby impeding formation of a fully functional immunological synapse, which finally results in a reduced suppressive potential.