Fosfomycin Uptake in Escherichia coli Is Mediated by the Outer-Membrane Porins OmpF, OmpC, and LamB.

The antibiotic fosfomycin (FOS) is widely recognized for the treatment of lower urinary tract infections with Escherichia coli and has lately gained importance as a therapeutic option to combat multidrug-resistant bacteria. However, resistance to FOS frequently develops through mutations reducing its uptake. Although the inner-membrane transport of FOS has been extensively studied in E. coli, its outer-membrane (OM) transport remains insufficiently understood. While evaluating minimal inhibitory concentrations in OM porin-deficient mutants, we observed that the E. coli ΔompFΔompC strain is four times more resistant to FOS than the wild type and the respective single mutants. Continuous monitoring of FOS-induced lysis of porin-deficient strains additionally highlighted the importance of LamB. The relevance of OmpF, OmpC, and LamB to FOS uptake was confirmed by electrophysiological and transcriptional analysis. Our study gives for the first time in-depth insight into the transport of FOS through the OM in E. coli.

Methamphetamine Induces Systemic Inflammation and Anxiety: The Role of the Gut-Immune-Brain Axis.

Methamphetamine (METH) is a highly addictive drug abused by millions of users worldwide, thus becoming a global health concern with limited management options. The inefficiency of existing treatment methods has driven research into understanding the mechanisms underlying METH-induced disorders and finding effective treatments. This study aims to understand the complex interactions of the gastrointestinal-immune-nervous systems following an acute METH dose administration as one of the potential underlying molecular mechanisms concentrating on the impact of METH abuse on gut permeability. Findings showed a decreased expression of tight junction proteins ZO-1 and EpCAm in intestinal tissue and the presence of FABP-1 in sera of METH treated mice suggests intestinal wall disruption. The increased presence of CD45+ immune cells in the intestinal wall further confirms gut wall inflammation/disruption. In the brain, the expression of inflammatory markers Ccl2, Cxcl1, IL-1ß, TMEM119, and the presence of albumin were higher in METH mice compared to shams, suggesting METH-induced blood-brain barrier disruption. In the spleen, cellular and gene changes are also noted. In addition, mice treated with an acute dose of METH showed anxious behavior in dark and light, open field, and elevated maze tests compared to sham controls. The findings on METH-induced inflammation and anxiety may provide opportunities to develop effective treatments for METH addiction in the future.

The development and physiological and pathophysiological functions of resident macrophages and glial cells.

In the past, brain function and the onset and progression of neurological diseases have been studied in a neuron-centric manner. However, in recent years the focus of many neuroscientists has shifted to other cell types that promote neurodevelopment and contribute to the functionality of neuronal networks in health and disease. Particularly microglia and astrocytes have been implicated in actively contributing to and controlling neuronal development, neuroinflammation, and neurodegeneration. Here, we summarize the development of brain-resident macrophages and astrocytes and their core functions in the developing brain. We discuss their contribution and intercellular crosstalk during tissue homeostasis and pathophysiology. We argue that in-depth knowledge of non-neuronal cells in the brain could provide novel therapeutic targets to reverse or contain neurological diseases.

Gluten sensitivity in a subset of children with insulin dependent diabetes mellitus.

OBJECTIVES: The association between celiac disease and insulin dependent diabetes mellitus (IDDM) is well established. Rectal gluten challenge has been used in patients with celiac disease and in first degree relatives as a tool to assess the mucosal immune response to gluten. The aim of this study was to assess the mucosal immune response to gluten in IDDM children by rectal gluten challenge. METHODS: Rectal biopsy specimens were obtained from 19 children with IDDM before and 6 h after rectal challenge with 2 g of a peptic tryptic digest of gliadin. A total of 16 treated celiac patients and 10 control subjects were also investigated. Epithelium and lamina propria CD3(+) and gamma delta(+) lymphocytes were counted with reference to a standard reference area of muscularis mucosae (10(4) microm(2)). RESULTS: After a local instillation of gliadin, a significant (>mean + 1 SD) percentage increment of lamina propria and epithelium CD3(+) and of lamina propria and epithelium gamma delta(+) lymphocytes was observed in five IDDM children, as compared to 11 and 13 celiac patients and one and two controls, respectively. A discriminant analysis allowed correct classification of 100% of patients with celiac disease and controls. The same analysis classified four of 19 IDDM children in the group of celiac patients. The positivity was associated with normal serology (antigliadin antibody, antiendomysial antibody, and antitissue transglutaminase antibodies) and a morphologically normal jejunal mucosa. All four patients had HLA-DQ alleles associated with celiac disease. CONCLUSIONS: Approximately 20% of IDDM children react to rectal instillation of gliadin. Long term follow-up is necessary to establish whether these subjects are at increased risk for developing celiac disease.