Necrosis drives susceptibility to Mycobacterium tuberculosis in POLG mtDNA mutator mice.

The genetic and molecular determinants that underlie the heterogeneity of Mycobacterium tuberculosis (Mtb) infection outcomes in humans are poorly understood. Multiple lines of evidence demonstrate that mitochondrial dysfunction can exacerbate mycobacterial disease severity and mutations in some mitochondrial genes confer susceptibility to mycobacterial infection in humans. Here, we report that mutations in mitochondria DNA (mtDNA) polymerase gamma (POLG) potentiate susceptibility to Mtb infection in mice. POLG mutator mtDNA mice fail to mount a protective innate immune response at an early infection timepoint, evidenced by high bacterial burdens, reduced M1 macrophages, and excessive neutrophil infiltration in the lungs. Immunohistochemistry reveals signs of enhanced necrosis in the lungs of Mtb-infected POLG mice and POLG mutator macrophages are hyper-susceptible to extrinsic triggers of necroptosis ex vivo. By assigning a role for mtDNA mutations in driving necrosis during Mtb infection, this work further highlights the requirement for mitochondrial homeostasis in mounting balanced immune responses to Mtb.

[Definition and illustration of the different types of nasal cycle using long-term rhinometry]. / Definition und Darstellung der verschiedenen Typen des Nasenzyklus mittels Langzeitrhinometrie.

BACKGROUND: A reciprocal swelling of the nasal mucosa is often referred to as the classical nasal cycle; however, reports in the literature suggest a more complex picture. Most of the research on the nasal cycle is based on individual measurements. The long-term rhinometry (LRM) now makes it possible to continuously examine the cyclic swelling of the nasal mucosa over 24 h. The aim of this study was therefore to evaluate the nasal cycle with LRM over 24 h. MATERIAL AND METHODS: An LRM was performed in 55 rhinologically healthy subjects over 24 h using the portable measuring system Rhino-Move© (Happersberger Otopront; Hohenstein, Germany). RESULTS: In addition to the expected strictly reciprocal swelling of the nasal mucosa in the sense of the classical nasal cycle, the following cycle types were detected: in-concert type with simultaneous rise and drop of the air flow on both sides of the nose, the one-sided type with significant congestion and decongestion of the mucous membrane only on one side and no detectable changes on the other side of the nose and the non-cycle type without any change in airflow on both sides. Most subjects showed a complex picture with multiple cycle types within the 24 h measurement (mixed nasal cycle). The types often differed during the day and night. CONCLUSION: This study confirms the assumption that the nasal cycle measured over 24 h is much more complex than often described in the literature. Most subjects showed several of the 5 cycle types described here. The LRM has proven to be an easy to- use and reliable measurement method. The relationship between cycle type and physical activity as well as other factors remains to be investigated.

Re-evaluating the nasal cycle by long-term rhinoflowmetry: most individuals demonstrate a 'mixed' nasal cycle.

BACKGROUND: The nasal cycle seems to be more complex than a strictly alternating swelling of the nasal mucosa. Long-term rhinoflowmetry (LRFM) allows continuous investigation of changes in nasal airflow over 24 hours (24h). We evaluated the various types of nasal cycle with LRFM over 24 hours and investigated the influence of age and gender. METHODS: LRFM was continuously performed over 24h in 55 rhinologically healthy subjects (36 female, 19 male). The LRFM flow curves were examined for phases of the 'classical' 'in-concert' 'one-side' and'no-cycle' cycle types. Subjects were divided into 4 age subgroups (19-29; 30-49; 50-69; >70 years). Correlations of age and gender with the individual cycle forms were analyzed. RESULTS: 85.5% of the subjects presented a 'mixed' nasal cycle within 24h. 'classical' nasal cycle was seen most often (92.7% vs. 'in-concert' 56.4% vs. 'one-sided' 18.2% vs. 'no-cycle' 5.5%). Older age groups significantly more often presented the 'no-cycle' type. A tendency was seen towards a mixed nasal cycle with increasing age. The mixed nasal cycle was significantly more often seen in the female subjects. CONCLUSIONS: LRFM is an easy-to-use measurement tool. The 'mixed' nasal cycle predominates. However, all 4 different cycle types can be detected, alternating over 24h in each subject. Moreover, the cycle type varies with age.

Sequence analysis of the catalytic subunit of H(+)-ATPase from porcine renal brush-border membranes.

The catalytic subunit of the H(+)-ATPase from brush-border membranes of porcine renal proximal tubules was labeled with the hydrophobic SH-group reagent 10-N-(bromoacetyl)amino-1-decyl-beta-glucopyranoside (BADG) which irreversibly inhibits proton pump activity in the absence but not in the presence of ATP. The labeled protein was purified and digested with proteinases. After isolation and sequencing of proteolytic peptides two BADG-labeled cysteines were identified. The amino acid sequences of the obtained proteolytic peptides were homologous to the catalytic subunit of V-ATPases. From mRNA of porcine kidney cortex a catalytic H(+)-ATPase subunit was cloned. 181 of the 183 amino acids which overlap in the sequence derived from the cDNA and the proteolytic peptides were identical, and the two deviations are due to single base exchanges. A comparison of the amino acid sequence derived from the cloned cDNA with sequences of catalytic H(+)-ATPase subunits communicated by other laboratories revealed 98%, 96% and 94% identity with sequences from bovine adrenal medulla, from bovine kidney medulla and from clathrin-coated vesicles of bovine brain. Between 64% and 69% identity was obtained with sequences from fungi and plants. The data show that the catalytic subunit of V-ATPases is highly conserved during evolution. They indicate organ and species specificity in mammalians.