Haem synthesis 220.127.116.11 Protoporphyrin levels 18.104.22.168 Coproporphyrin levels 22.214.171.124 delta-Aminolaevulinic acid levels in urine and blood 126.96.36.199 Aminolaevulinic acid dehydratase levels 188.8.131.52 delta-Aminolaevulinic acid synthase 184.108.40.206 Other effects of decreased haem synthesis
Small amounts of zinc 5X10-6 M stimulate rapid axonal transport of proteins in an in vitro system using frog ganglia and nerve (Edstrom and Mattsson, 1975). Zinc probably stimulates axonal transport by stabilizing rat brain microtubules and ribosomes (Edstrorn and Mattsson, 1975). Zinc, at concentration of 5X10-6 increased synthesis to 140 percent of the control and protein transport to 175 percent of the control value. In certain concentrations, Zn appears to be important for both protein synthesis and axoplasmic flow. Metal chelation of Zn causes nerve degeneration, while Zn toxicity causes fast axonal transport resulting in a distal concentration of membrane protein which may proceed to defective maintenance of axon terminal structures and loss of function.
In summary, the use of experimental evolution, fitness determinations and full-length genomic sequencing has allowed us to test the theoretical predictions regarding the cost of specialization. There was no correlation between the selective conditions and niche width of evolved populations, a significant fraction of the mutations carried no cost, and tradeoffs were the result of antagonistic pleiotropy. Among the mutations most likely to result in antagonistic pleiotropy we identified extensive modifications of the regulatory sequences at the 3′ end of the genome and in N and P proteins, so the cost of specialization may be the result of changes in the regulation of RNA synthesis.
Zinc deficiency has been shown to impair DNA, RNA and protein synthesis in the brains of suckling rats (Fosmire et al., 1975). Zinc deficiency results in impaired incorporation of thymidine into brain DNA. Incorporation of sulfur into protein is also decreased. Zinc deficiency also decreases the concentration of total lipid in brain while phospholipids and fatty acids are not affected.
The modifications in the 3′ termini of A25 and P25 are likely to change the levels of RNA synthesis, which also requires P and N proteins (as well as L). The parallel P protein mutation found in A25 and P25 genotypes (Threonine 142→Methionine) map in the central domain that mediates oligomerization. Replication requires the formation of tetramers; , and mutations in this domain cause severe inhibition of P protein function. The N protein does not seem to be involved in the transcription (except as part of the template), but it is required for replication. N proteins tend to aggregate and their availability in a functional form depends on interactions with P protein. While there are no studies regarding RNA synthesis in sand fly cells, persistent VSV infection of Drosophila cells results in dramatic changes in the relative amount of mRNA and progeny genomes compared to those generated during replication in mammalian cells; ; ; . Production of leader RNA, which is involved in cellular gene expression shut-off, decreases nearly two orders of magnitude, and its transport into the nucleus is inhibited. Both synthesis of mRNA and synthesis of progeny genomes are downregulated after an initial burst and stay at low but constant levels for the duration of persistence. Overall, replication is promoted over transcription. Based on our results and these studies on RNA synthesis during insect cell infections we propose that adaptation to persistent infect infection is accomplished by the mutations found in the 3′ termini together with the N and P parallel mutations through changes in the regulation of synthesis of different RNA species (mRNA, antigenomes and genomes). These changes in the pattern of RNA synthesis would be the cause of fitness loss in BHK-21 cells.
(1991), particularly the effects of lead on hormone action, competition with calcium binding on calcium messenger systems, and the impaired synthesis of collagen or sialoproteins.
Mild dysfunction of the liver has been reported among Soviet workers engaged in the production of Na-PCP (Vinogradova et al., 1973) including, for example, a reduced ability to synthesize protein.
It has been suggested that delay in the accumulation of haemoproteins of the respiratory chain in brain tissue during development may result in decreased synthesis of haem enzymes in the brain (Bull, 1980; Moore et al., 1987).
The schizophrenias are biochemically numerous, so the simplistic term “schizophrenia” should be avoided. At least seven different biochemical imbalances can produce clinical symptoms which are indistinguishable by the so-called research diagnostic criteria for simplistic schizophrenia. As an example, Wilson’s disease, a Cu overload disorder, can be marked by psychosis and hallucinations. Oral zinc has an antagonistic effect on the reabsorption of Cu in the gastrointestinal tract and, for that reason, is considered valuable in the treatment of this disease (Hoogenraad et al., 1978). We have already mentioned the work of Derrien and Benoit (1929), and Kimura and Kumura (1969) who suggested or found Zn to be involved in mental disease. In 1967 Pfeiffer and Iliev reported low blood histamine levels in schizophrenic patients histamine is stored with zinc. A definite percentage of psychiatric patients have been found to have the chemical kryptopyrrole in their urine. Kryptopyrrole reacts avidly with all aldehyde chemicals, including pyridoxal (Pfeiffer et al., 1974). The resulting kryptopyrrole-pyridoxal complex by chelating Zn produces a Zn deficiency as well as a severe pyridoxine deficiency. These patients, whom we have termed pyroluric, respond for the most part to vitamin B6 and Zn therapy (Pfeiffer and Bacchi, 1975; Pfeiffer, 1976). Pyroluria is a form of schizophrenic porphyria, similar to acute intermittent porphyria where both pyrroles and porphyrins are excreted in the urine in excess (Braverman, 1978). Both Zn, ALA dehydratase, vitamin B6 , and ALA synthetase, are important co-factors in the pyrrole porphyriaheme pathway.
The steps within the haem biosynthetic pathway which have been used to measure effect are: 1) inhibition of delta-aminolaevulinic acid dehydratase (ALAD); 2) urinary excretion of delta-aminolaevulinic acid (ALAU); (3) the accumulation of zinc protoporphyrin (ZPP) in erythrocytes arising from the inhibition of the enzyme ferrochelatase or the iron transport system.
Zinc deficiency and thyroid hormone shortage occurring in both cretinism and myxedema have similar signs, ie. retarded growth, reduced appetite and activity, impaired development of skin and hair (Hartoma et al., 1979). Zinc deficiency symptoms may be mediated by excess glucocorticoids since Zn depletion results in elevation of glucocorticoids. Elevated glucocorticoids and Zn deficiency both result in death of thymic lymphocytes (Donovan and Thomas, 1980). A deficiency of nerve growth factor may occur with Zn deficiency. One nerve growth factor is a small basic protein with three distinct types of sub-units (Vinores and Guroff, 1980). Two molecules of Zn are present in the complex and Zn participates in holding the structure together (Dunn et al., 1980; Pattison and Dunn, 1975). In the absence of Zn the subunits separate. Nerve growth factor is required for the survival and development of certain sympathetic and sensory neurons. It is equally clear that nerve growth factor affects a wide variety of other cells as well. Nerve growth factors are present on the plasma membrane and almost certainly at the synaptic ending as well (Dunn et al., 1980). Nerve growth factor action increased dendritic attachments which requires elevated levels of RNA synthesis, which is Zn dependant.
Surprisingly, when sequencing the NSs gene, that encodes the virulence factor responsible for a general inhibition of cellular RNA synthesis and IFN-ß production, we found that single-host adapted viruses presented large deletions in this gene. Virus passaged in mammalian BHK21 cells defective in IFN-a/b signaling had a deletion of 259 nt introducing a stop-codon in the NSs gene. The resulting protein was shortened to 60 amino-acids instead of 265. Virus passaged in mosquito Aag2 cells showed a deletion of 73 nt, again with a stop-codon, causing a shortening of the NSs protein to 131 amino-acids. These two distinct deletions in the NSs gene following 30 serial passages in each cell type suggest that the viral genome may function differently depending on whether replication is in mammalian or mosquito cells. Thus, while serial passages of RVFV in a single cell type selected for a virus with a truncated NSs gene specific to that cell type, alternating passages did not allow the emergence of deletions in the NSs gene. Indeed, like the parental P strain, the 30th alternating passage virus Z30Alt did not present any major genetic changes in the NSs gene. The fact that the NSs gene is dispensable in both single host systems suggests that other mutations are involved in the host adaptation process. Thus, the different non-synonymous mutations identified in the segments M and L should be further explored in this context, particularly since they are mostly specialized depending on host. It is likely that these kinds of deletion events take place spontaneously during viral replication and are selected only in the absence of alternation. Further experiments involving independent serial passages would permit to evaluate the frequency at which the phenomenon occurs. Deletions in the NSs gene have been described in a naturally attenuated RVFV (Clone 13) purified from a nonfatal human case in the Central African Republic . This strain has a large internal deletion of 549 nt in the NSs gene (~70% of its length). Animals can survive high infectious doses of Clone 13, up to 106 PFU, without developing any symptoms. Furthermore, Clone 13 has been tested as a vaccine candidate in sheep and cattle that can indeed then elicit a protective response against challenge with a virulent RVFV strain. When the clones we obtained after 30 serial passages in a single cell type were inoculated into mice (at 104 PFU), the animals survived for 21 days and developed protective IgG against challenge with a virulent strain of RVFV. Moreover, most mice inoculated with Z30Alt (isolated at the 30th alternating passage) died 2 days later than did those treated with the parental P strain, and one mouse survived virus inoculation. Having said that, it is known that the outcome of infection is mainly determined by a balance between the rate of viral replication and the immune response, which together limit viral spread . This might explain why one of five mice recovered from infection. Nevertheless, the 30th alternating passage virus Z30Alt retained roughly the same level of virulence as the parental P strain owing to the maintenance of NSs integrity.