Effects of MMP-9 inhibition by doxycycline on proteome of lungs in high tidal volume mechanical ventilation-induced acute lung injury

Background  

Although mechanical ventilation (MV) is a major supportive therapy for patients with acute respiratory distress syndrome, it may result in side effects including lung injury. In this study we hypothesize that MMP-9 inhibition by doxycycline might reduce MV-related lung damage. Using a proteomic approach we identified the pulmonary proteins altered in high volume ventilation-induced lung injury (VILI). Forty Wistar rats were randomized to an orally pretreated with doxycycline group (n = 20) or to a placebo group (n = 20) each of which was followed by instrumentation prior to either low or high tidal volume mechanical ventilation. Afterwards, animals were euthanized and lungs were harvested for subsequent analyses.     

Isolation of avian paramyxovirus 1 from a patient with a lethal case of pneumonia

An unknown virus was isolated from a lung biopsy sample and multiple other samples from a patient who developed a lethal case of pneumonia following a peripheral blood stem cell transplant. A random PCR-based molecular screening method was used to identify the infectious agent as avian paramyxovirus 1 (APMV-1; a group encompassing Newcastle disease virus), which is a highly contagious poultry pathogen that has only rarely been found in human infections. Immunohistochemical analysis confirmed the presence of APMV-1 antigen in sloughed alveolar cells in lung tissue from autopsy. Sequence from the human isolate showed that it was most closely related to virulent pigeon strains of APMV-1. This is the most completely documented case of a systemic human infection caused by APMV-1 and is the first report of an association between this virus and a fatal disease in a human.     

The genetic basis of individual-recognition signals in the mouse

The major histocompatibility complex (MHC) is widely assumed to be a primary determinant of individual-recognition scents in many vertebrates [1-6], but there has been no functional test of this in animals with normal levels of genetic variation. Mice have evolved another polygenic and highly polymorphic set of proteins for scent communication, the major urinary proteins (MUPs) [7-12], which may provide a more reliable identity signature ([13, 14] and A.L. Sherborne, M.D.T., S. Paterson, F.J., W.E.R.O., P. Stockley, R.J.B., and J.L.H., unpublished data). We used female preference for males that countermark competitor male scents [15-17] to test the ability of wild-derived mice to recognize individual males differing in MHC or MUP type on a variable genetic background. Differences in MHC type were not used for individual recognition. Instead, recognition depended on a difference in MUP type, regardless of other genetic differences between individuals. Recognition also required scent contact, consistent with detection of involatile components through the vomeronasal system [6, 18]. Other differences in individual scent stimulated investigation but did not result in individual recognition. Contrary to untested assumptions of a vertebrate-wide mechanism based largely on MHC variation, mice use a species-specific [12] individual identity signature that can be recognized reliably despite the complex internal and external factors that influence scents [2]. Specific signals for genetic identity recognition in other species now need to be investigated.     

The genetic basis of inbreeding avoidance in house mice

Animals might be able to use highly polymorphic genetic markers to recognize very close relatives and avoid inbreeding. The major histocompatibility complex (MHC) is thought to provide such a marker because it influences individual scent in a broad range of vertebrates. However, direct evidence is very limited. In house mice (Mus musculus domesticus), the major urinary protein (MUP) gene cluster provides another highly polymorphic scent signal of genetic identity that could underlie kin recognition. We demonstrate that wild mice breeding freely in seminatural enclosures show no avoidance of mates with the same MHC genotype when genome-wide similarity is controlled. Instead, inbreeding avoidance is fully explained by a strong deficit in successful matings between mice sharing both MUP haplotypes. Single haplotype sharing is not a good guide to the identification of full sibs, and there was no evidence of behavioral imprinting on maternal MHC or MUP haplotypes. This study, the first to examine wild animals with normal variation in MHC, MUP, and genetic background, demonstrates that mice use self-referent matching of a species-specific polymorphic signal to avoid inbreeding. Recognition of close kin as unsuitable mates might be more variable across species than a generic vertebrate-wide ability to avoid inbreeding based on MHC.     

Exonic splicing regulatory elements skew synonymous codon usage near intron-exon boundaries in mammals

In mammals there is a bias in amino acid usage near splice sites that is explained, in large part, by the high density of exonic splicing enhancers (ESEs) in these regions. Is there a similar bias for the relative use of synonymous codons, and can any such bias be predicted by their abundance in ESEs? Prior reports suggested that such trends may exist. From analysis of human exons, we find that 47 of the 59 codons with at least one synonym show differential usage in the proximity of exon ends, of which 42 remain significant after correction for multiple testing. Within sets of synonymous codons those more preferred near splice sites are generally those that are relatively more abundant within the ESEs. However, the examples given previously appear exceptionally good fits and there exist many exceptions, the usage of lysine's codons being a case in point. Similar results are observed in mouse exons. We conclude that splice regulation impacts on the choice of synonymous codons in mammals, but the magnitude of this effect is less than might at first have been supposed.     

Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation

Background  

In general, inflammation plays a role in most bladder pathologies and represents a defense reaction to injury that often times is two edged. In particular, bladder neurogenic inflammation involves the participation of mast cells and sensory nerves. Increased mast cell numbers and tryptase release represent one of the prevalent etiologic theories for interstitial cystitis and other urinary bladder inflammatory conditions. The activity of mast cell-derived tryptase as well as thrombin is significantly increased during inflammation. Those enzymes activate specific G-protein coupled proteinase-activated receptors (PAR)s.     

Metabolic Adaptations of Azospirillum brasilense to Oxygen Stress by Cell-to-Cell Clumping and Flocculation

The ability of bacteria to monitor their metabolism and adjust their behavior accordingly is critical to maintain competitiveness in the environment. The motile microaerophilic bacterium Azospirillum brasilense navigates oxygen gradients by aerotaxis in order to locate low oxygen concentrations that can support metabolism. When cells are exposed to elevated levels of oxygen in their surroundings, motile A. brasilense cells implement an alternative response to aerotaxis and form transient clumps by cell-to-cell interactions. Clumping was suggested to represent a behavior protecting motile cells from transiently elevated levels of aeration. Using the proteomics of wild-type and mutant strains affected in the extent of their clumping abilities, we show that cell-to-cell clumping represents a metabolic scavenging strategy that likely prepares the cells for further metabolic stresses. Analysis of mutants affected in carbon or nitrogen metabolism confirmed this assumption. The metabolic changes experienced as clumping progresses prime cells for flocculation, a morphological and metabolic shift of cells triggered under elevated-aeration conditions and nitrogen limitation. The analysis of various mutants during clumping and flocculation characterized an ordered set of changes in cell envelope properties accompanying the metabolic changes. These data also identify clumping and early flocculation to be behaviors compatible with the expression of nitrogen fixation genes, despite the elevated-aeration conditions. Cell-to-cell clumping may thus license diazotrophy to microaerophilic A. brasilense cells under elevated oxygen conditions and prime them for long-term survival via flocculation if metabolic stress persists.