Tag Archives: Otamixaban

ORF was found to be the predominant place of non

ORF5 was found to be the predominant place of non-synonymous substitutions during circulation of TSPyV in human population (this study) as well as the most profound genomic changes of Ortho-I polyomaviruses during their divergence in many hosts (Carter et al., 2013; Lauber et al., 2015). Despite being exceptional, the Otamixaban of ORF5 is evidently coordinated with that of other regions at both intra- and inter-polyomavirus species levels. We identified sets of covarying sites representing ORF5 and VP1, and ORF5, ORF2 and NCCR regions of the TSPyV genome, and we (Lauber et al., 2015) and others (Carter et al., 2013) observed a phylogenetic association of ORF5 with most conserved genome regions in the majority of Ortho-I polyomaviruses. This agreement at the levels of micro- and macro-evolution reveals that ORF5 deserves further studies.
First, two of these substitutions (242 and 280) were accepted during transition between some of the most deeply rooted intermediate ancestors leading to two major contemporary lineages of TSPyV (TSI and TSII), while the third one (245) more likely than less may have mutated very early. Second, all three substitutions are genetically segregated within a small region of 114 nts (~2.5% of the genome) rather than scattered over the genome as would be expected under neutral evolution. Third, they are observed in a single ORF, ORF5, while three other ORFs, ORF2-ORF4, remain unaffected. Fourth, under the model of neutral evolution and with the constraints imposed by ORF5 codons, the frequency of synonymous substitution in the ORF2 region overlapping with ORF5 is expected to be lower than that in the downstream part of ORF2, according to prior research with overlapping genes (Miyata and Yasunaga, 1978; Sabath et al., 2012). However, these frequencies in the two regions are rather similar in TSPyV: 6.7 and 6.2 per 1000 nts of the ORF2/ORF5 overlap and the ORF2-only, respectively. Fifth and finally, the A245V variation corresponds to the recently described toggling at the COCO-VA site, which was found to be accelerated and under positive selection in a large panel of Ortho-I polyomavirus species during inter-species evolution (Lauber et al., 2015). According to the model of neutral evolution of the COCO-VA toggling developed in that study, the toggling is highly Otamixaban unlikely due to chance to observe during intra-species divergence of a polyomavirus.

Material and methods

The authors thank Ernst Verschoor for providing the dates of OraPyV isolations, Hans van Leeuwen for the useful discussions, and Igor Sidorov and Dmitry Samborskiy for help with Viralis. A.E.G. is member of the Netherlands Bioinformatics Center (NBIC) Faculty. This study was funded by the Leiden University Medical Center, The Netherlands, partially through the Collaborative Agreement in Bioinformatics between Leiden University Medical Center and Moscow State University (MoBiLe), and Leiden University Fund.

Measles virus (MV) is a member of the genus Morbillivirus within the family Paramyxoviridae. The MV genome is 15,894 bases, forming a nonsegmented, single-stranded, negative-sense RNA molecule encoding six genes: N (nucleocapsid), P (phospho), M (matrix), F (fusion), H (hemagglutinin), and L (large). It also contains leader and trailer sequences at its 3′ and 5′ termini, respectively (Griffin, 2013).
Subacute sclerosing panencephalitis (SSPE) is a fatal neurologic complication of persistent MV infection in the brain (Schneider-Schaulies et al., 2003). SSPE occurs in about 16 cases per one million cases of measles in Japan (Okuno et al., 1989), although a US study reported that SSPE develops in about 220 cases per one million cases of measles (Bellini et al., 2005). MV isolates from the brains of patients with SSPE differ from those from the nasal or blood specimens of patients with acute measles, and SSPE strains are known to contain many mutations in their genomes (Ayata et al., 1989; Cattaneo et al., 1988a, 1988b; Schmid et al., 1992). Therefore, it is important to investigate the influence of these mutations and to understand the molecular mechanisms of MV persistence and the pathogenesis of SSPE. SSPE strains cause neurologic disease in rodents, including hamsters and mice, following their intracerebral inoculation (Albrecht et al., 1977; Johnson and Byington, 1971, 1977; Katz et al., 1970; Sugita, et al., 1984; Thormar et al., 1977).

Pathogenesis from members within Alphabaculovirus

Pathogenesis from members within Alphabaculovirus and Betabaculovirus may differ, although fewer studies have described betabaculovirus pathogenesis. Briefly, alphabaculoviruses and betabaculoviruses infect the midgut epithelium of insect hosts. In alphabaculoviruses, virions reach tissues in the insect hemocoel producing more virions. The product of the very late gene P10 is responsible for nuclear lysis (van Oers et al., 1993), releasing ODV in the environment after the insect cadaver liquefies. In betabaculoviruses, the nucleus of infected Otamixaban enlarges, followed by nuclear membrane breakage. The genes and mechanisms affecting this early nuclear membrane rupture are not known. Nucleocapsids are then enveloped and occluded in this nucleocytoplasmic compartment. Betabaculovirus pathogenesis differs in tissue tropism, from viruses being midgut restricted, to infecting midgut epithelium and fat body tissue, to infecting several tissues of the host. In addition, dispersal of ODV may differ from dispersal in diarrheal secretions to dispersal following complete insect liquefaction (reviewed Otamixaban in Federici, 1997).
Degradative enzymes have been reported in baculoviruses, including viral-chitinase (v-chitinase) which digests chitin, the main component of the insect exoskeleton; and viral-cathepsin (v-cathepsin), which is involved in the degradation of internal larval tissues (Ohkawa et al., 1994; Slack et al., 1995). The concerted activity of these two enzymes enables host liquefaction which allows virus release from the infected cadaver and dissemination to other hosts (Hawtin et al., 1997; Kang et al., 1998a). The betabaculovirus Cydia pomonella granulovirus (CpGV) v-cathepsin was shown to be a functional protease and necessary for larval melanization and liquefaction or softening of larval cadavers, depending on the virus background in which it was tested (Hilton et al., 2008; Kang et al., 1998b). Similarly, the CpGV v-chitinase expressed from a Bombyx mori NPV (BmNPV) recombinant virus allowed larval liquefaction and interacted with BmNPV v-cathepsin (Daimon et al., 2007).
The role of another degradative enzyme, the viral MMP, found in betabaculoviruses, has not been studied extensively. To date, there is only one functional study on baculovirus MMPs, characterizing the Xestia c-nigrum granulovirus (XcGV) MMP (XcGV-MMP). XcGV-MMP is a functional MMP involved in larval melanization and thought to have a role in degradation of host basement membranes during the late stages of infection (Ko et al., 2000). Open reading 46 (ORF46) encoded in the CpGV genome predicts a protein, CpGV-MMP, which shows significant similarity to MMPs (Luque et al., 2001). However, its role in viral pathogenesis has not been described.



Materials and methods

We are grateful to Anna C. Rogers for preliminary results, cloning CpGV-ORF46 from the CpGV genome, and providing other reagents. We thank Monique van Oers, Susuma Katsuma, and Jeffrey Slack for providing Ac-ΔCCBac, anti-chitinase serum, and Cath (-), respectively.
This work was supported in part by the National Institutes of Health Award 5RO1AI091972-3 to A. L. P. This is contribution number 15-186-J from the Kansas Agricultural Experiment Station.

It is well known that mammalian influenza viruses undergo antigenic drift through acquisition of amino acid substitutions within the viral glycoproteins haemagglutinin (HA) and neuraminidase (NA), leading to the occurrence of disease epidemics. For this reason, vaccine strains to influenza viruses eventually become ineffective, unless they are updated regularly. The HA1 domain appears to be under the most selective pressure, consistent with its role in induction of neutralising antibodies (Nelson and Holmes, 2007). Substitutions in human H3 viruses have been associated with changes in charge, acquisition of glycosylation sites and also alteration of receptor binding avidity (Blackburne et al., 2008; Kobayashi and Suzuki, 2012; Lin et al., 2012). Changes in HA are often accompanied by substitutions in NA and it is believed that the activity of HA and NA should be balanced (Mitnaul et al., 2000; Kaverin et al., 1998; Baigent and McCauley, 2001). The rate of antigenic change differs between influenza viruses of different species: human H3N2 viruses appear to drift more rapidly than either swine H3N2 or equine H3N8 viruses, as assayed by haemagglutination inhibition (HI) with ferret antisera. This has been demonstrated by antigenic cartography, which indicated that human H3N2 viruses underwent multiple ‘cluster jumps’ between 1968 and 2003 (Smith et al., 2004) whereas equine and swine viruses evolved fewer antigenic clusters over a similar period of time (de Jong et al., 2007; Lewis et al., 2011).

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Our study determined the average excursion of the diaphragms during tidal breathing in a standing position in a health screening center cohort using dynamic chest radiography (“dynamic X-ray phrenicography”). These findings are important because they provide reference values of diaphragmatic motion during tidal breathing useful for the diagnosis of diseases related to respiratory kinetics. Our study also suggests that dynamic X-ray phrenicography is a useful method for the quantitative evaluation of diaphragmatic motion with a radiation dose comparable to conventional posteroanterior chest radiography (22).

Our study demonstrated that the average excursions of the bilateral Otamixaban during tidal breathing (right: 11.0 mm, 95% CI 10.4 to 11.6 mm; left: 14.9 mm, 95% CI 14.2 to 15.5 mm) were numerically less than those during forced breathing in previous studies using other modalities 2; 7 ;  8. Using fluoroscopy, Alexander reported that the average right excursion was 27.5 mm and the average left excursion was 31.5 mm during forced breathing in the standing position in 127 patients (2). Using ultrasound, Harris et al. reported that the average right diaphragm excursion was 48 mm during forced breathing in the supine position in 53 healthy adults (7). Using MR fluoroscopy, Gierada et al. reported that the average right excursion was 44 mm and the average left excursion was 42 mm during forced breathing in the supine position in 10 healthy volunteers (8). The difference in diaphragmatic excursion during tidal breathing versus forced breathing is unsurprising.

Our study showed that the excursion and peak motion speed of the left diaphragm are significantly greater and faster than those of the right. With regard to the excursion, the results of our study are consistent with those of previous reports using fluoroscopy in a standing position 2 ;  3. However, in the previous studies evaluating diaphragmatic motion in the supine position, the asymmetric diaphragmatic motion was not mentioned 7 ;  8. The asymmetric excursion of the bilateral diaphragm may be more apparent in the standing position, but may not be detectable or may disappear in the supine position. Although we cannot explain the reason for the asymmetry in diaphragmatic motion, we speculate that the presence of the liver may limit the excursion of the right diaphragm. Regarding the motion speed, to the best of our knowledge this study is the first to evaluate it. The faster motion speed of the left diaphragm compared to that of the right diaphragm would be related to the greater excursion of the left diaphragm.

We found that higher BMI and higher tidal volume were independently associated with the increased excursions of the bilateral diaphragm by both univariate and multivariate analyses, although the strength of these associations was weak. We cannot explain the exact reason for the correlation between BMI and the excursion of the diaphragm. However, a previous study showed that BMI is associated with peak oxygen consumption (23), and the increased oxygen consumption in an obese participant may affect diaphragmatic movement. Another possible reason is that lower thoracic compliance due to higher BMI may cause increased movement of the diaphragm for compensation. Regarding the correlation between tidal volume and excursion of the diaphragm, given that diaphragmatic muscle serves as the most important respiratory muscle, the result is to be expected. Considering our results, the excursion evaluated by dynamic X-ray phrenicography could potentially predict tidal volume.

Our study has several limitations. First, we included only 172 volunteers, and additional studies on larger participant populations are required to confirm these preliminary findings. Second, we evaluated only the motion of the highest point of the diaphragms for the sake of simplicity, and three-dimensional motion of the diaphragm could not be completely reflected in our results. However, we believe that this simple method would be practical and more easily applicable in a clinical setting.