Activation of type I and III interferon signalling pathways occurs in lung epithelial cells infected with low pathogenic avian influenza viruses

The host response to the low pathogenic avian influenza (LPAI) H5N2, H5N3 and H9N2 viruses were examined in A549, MDCK, and CEF cells using a systems-based approach. The H5N2 and H5N3 viruses replicated efficiently in A549 and MDCK cells, while the H9N2 virus replicated least efficiently in these cell types. However, all LPAI viruses exhibited similar and higher replication efficiencies in CEF cells. A comparison of the host responses of these viruses and the H1N1/WSN virus and low passage pH1N1 clinical isolates was performed in A549 cells. The H9N2 and H5N2 virus subtypes exhibited a robust induction of Type I and Type III interferon (IFN) expression, sustained STAT1 activation from between 3 and 6 hpi, which correlated with large increases in IFN-stimulated gene (ISG) expression by 10 hpi. In contrast, cells infected with the pH1N1 or H1N1/WSN virus showed only small increases in Type III IFN signalling, low levels of ISG expression, and down-regulated expression of the IFN type I receptor. JNK activation and increased expression of the pro-apoptotic XAF1 protein was observed in A549 cells infected with all viruses except the H1N1/WSN virus, while MAPK p38 activation was only observed in cells infected with the pH1N1 and the H5 virus subtypes. No IFN expression and low ISG expression levels were generally observed in CEF cells infected with either AIV, while increased IFN and ISG expression was observed in response to the H1N1/WSN infection. These data suggest differences in the replication characteristics and antivirus signalling responses both among the different LPAI viruses, and between these viruses and the H1N1 viruses examined. These virus-specific differences in host cell signalling highlight the importance of examining the host response to avian influenza viruses that have not been extensively adapted to mammalian tissue culture.     

Kynurenines: from the perspective of major psychiatric disorders

Psychiatric disorders are documented to be associated with a mild pro-inflammatory state. Pro-inflammatory mediators could activate the tryptophan breakdown and kynurenine pathway with a shift toward the neurotoxic arm where excitotoxic N-methyl-D-aspartate receptor agonist quinolinic acid is formed. An unbalanced metabolism in terms of neuroprotective and neurotoxic effects, such as reduced kynurenic acid to kynurenine ratio, has been demonstrated in the major psychiatric disorders such as unipolar depression, bipolar manic-depressive disorder and schizophrenia, and in drug-induced neuropsychiatric side effects such as interferon-α treated patients. The changes in serum or plasma are shown to be associated with central changes such as in the cerebrospinal fluid and certain brain areas. While currently available antidepressants and mood stabilizers could not efficiently improve these neurochemical changes within the same period that could induce clinical improvement, some antipsychotic treatments could reverse certain metabolic imbalances. Some of these changes were tested also in animal models. In this review the role of this unbalanced kynurenine metabolism through interactions with other neurochemicals is discussed as a major contributing pathophysiological mechanism in psychiatric disorders. Moreover, the biomarker role of kynurenine metabolites and future therapeutic opportunities are also discussed.     

Identification of Rhizobium plasmid sequences involved in recognition of Psophocarpus, Vigna, and other legumes

Symbiotic DNA sequences involved in nodulation by Rhizobium must include genes responsible for recognizing homologous hosts. We sought these genes by mobilizing the symbiotic plasmid of a broad host-range Rhizobium MPIK3030 (= NGR234) that can nodulate Glycine max, Psophocarpus tetragonolobus, Vigna unguiculata, etc., into two Nod- Rhizobium mutants as well as into Agrobacterium tumefaciens. Subsequently, cosmid clones of pMPIK3030a were mobilized into Nod+ Rhizobium that cannot nodulate the chosen hosts. Nodule development was monitored by examining the ultrastructure of nodules formed by the transconjugants. pMPIK3030a could complement Nod- and Nif- deletions in R. leguminosarum and R. meliloti as well as enable A. tumefaciens to nodulate. Three non-overlapping sets of cosmids were found that conferred upon a slow-growing Rhizobium species, as well as on R. loti and R. meliloti, the ability to nodulate Psophocarpus and Vigna, thus pointing to the existence of three sets of host-specificity genes. Recipients harboring these hsn regions had truly broadened host-range since they could nodulate both their original hosts as well as MPIK3030 hosts.     

Gain in functions of mutant Cu,Zn-superoxide dismutases as a causative factor in familial amyotrophic lateral sclerosis: less reactive oxidant formation but high spontaneous aggregation and precipitation

Eight mutant Cu,Zn-superoxide dismutases (SODs) related to familial amyotrophic lateral sclerosis (FALS) were produced in a baculovirus/insect cell expression system and their molecular properties in terms of hydroxyl radical formation and aggregation were compared with the wild-type enzyme. Treatment of the enzymes with Chelex 100 resin decreased Cu contents as well as SOD activities in all mutant Cu,Zn-SODs, indicating that the affinities of the enzymes for copper ion were decreased. Contrary to previous reports, all the mutant Cu,Zn-SODs exhibited less reactive oxidant producing ability in the presence of hydrogen peroxide than the wild-type enzyme. Both SOD activities and their reactive oxidant forming correlated well with the copper ion content of the molecules. In addition, the proteins spontaneously aggregated and were precipitated by simple centrifugation at 12,000g for 20 min in keeping their enzyme activities. Since hyaline inclusions found in FALS patients with SOD1 mutations contained components which were reactive to anti-Cu,Zn-SOD antibody, a primary reaction caused by mutant SOD1 may be attributed to their propensity to form aggregates. Aggregated but still active mutant SOD1 would be expected to mediate the formation of reactive oxygen species and nitrosylation in a more condensed state.     

Overall Prevalence and Distribution of Knockdown Resistance (kdr) Mutations in Aedes aegypti from Mandalay Region,Myanmar

Knockdown resistance (kdr) mutations in the voltage-gated sodium channel (VGSC) of mosquitoes confer resistance to insecticides. Although insecticide resistance has been suspected to be widespread in the natural population of Aedes aegypti in Myanmar, only limited information is currently available. The overall prevalence and distribution of kdr mutations was analyzed in Ae. aegypti from Mandalay areas, Myanmar. Sequence analysis of the VGSC in Ae. aegypti from Myanmar revealed amino acid mutations at 13 and 11 positions in domains II and III of VGSC, respectively. High frequencies of S989P (68.6%), V1016G (73.5%), and F1534C (40.1%) were found in domains II and III. T1520I was also found, but the frequency was low (8.1%). The frequency of S989P/V1016G was high (55.0%), and the frequencies of V1016G/F1534C and S989P/V1016G/F1534C were also high at 30.1% and 23.5%, respectively. Novel mutations in domain II (L963Q, M976I, V977A, M994T, L995F, V996M/A, D998N, V999A, N1013D, and F1020S) and domain III (K1514R, Y1523H, V1529A, F1534L, F1537S, V1546A, F1551S, G1581D, and K1584R) were also identified. These results collectively suggest that high frequencies of kdr mutations were identified in Myanmar Ae. aegypti, indicating a high level of insecticide resistance.     

Modeling population viability of captive elephants in Myanmar (Burma): implications for wild populations

Captive Asian elephants Elephas maximus , used as work animals, constitute up to 22–30% of remaining Asian elephants. Myanmar has the largest captive population worldwide (∼6000), maintained at this level for over a century. We used published demographic data to assess the viability of this captive population. We tested how this population can be self-sustained, how many elephants must be supplemented from the wild to maintain it, and what consequences live capture may have for Myanmar's wild population. Our results demonstrate that the current captive population is not self-sustaining because mortality is too high and birth rates are too low. Our models also suggest ∼100 elephants year⁻¹ have been captured in the wild to supplement the captive population. Such supplementation cannot be supported by a wild population of fewer than 4000 elephants. Given the most recent expert estimate of ∼2000 wild elephants remaining in Myanmar, a harvest of 100 elephants year⁻¹ could result in extinction of the wild population in 31 years. Continued live capture threatens the survival of wild and captive populations and must stop. In addition, captive breeding should be increased. These measures are essential to slow the decline and extinction of all of Myanmar's elephants.