Prion channel proteins and their role in vacuolation and neurodegenerative diseases

The prion encephalopathies, which are characterized by neuropathological changes that include vacuolation, astrocytosis, the development of amyloid plaques and neuronal loss, are associated with the conversion of a normal cellular isoform of prion protein (PrP(c)) to an abnormal pathologic scrapie isoform (PrP(Sc)). The use of PrP[106-126] and its isoforms in studies of channels in lipid bilayers has revealed that it forms heterogeneous channels reflecting modifications in the peptide's structure and differences in the properties of the formed oligomeric aggregates and their intermediates. We propose that the accumulation of pathological isoforms of prion are linked to membrane abnormalities and vacuolation in prion diseases. The interlinked changes in membrane fluidity and endogenous channels induced by prion isoforms can occur independently and concurrently with channel formation, i.e. they are not mutually exclusive. We suggest that vacuolation is a cellular response triggered in order to immobilize pathological prion isoforms having the ability to form channels that compromise cellular membranes. This mechanism is similar to that of other channel-forming proteins that induce vacuolation, e.g. the well-established VacA of Helicobacter pylori, Vero cells and aerolysin, as well as melittin-induced micellization and membrane fusion. We conclude that channel formation is part of the molecular mechanisms responsible for the vacuolation associated with prion diseases. The initial vacuolation could be an adaptive cellular response to compartmentalize the increase in pathogenic prion isoforms, while an excessive accumulation of pathologic prion isoforms in later stages represents the inability of the cell to continue to compartmentalize these misfolded proteins in vacuoles.     

The potential role of ubiquitin c-terminal hydrolases in oncogenesis

Deubiquitinating enzymes (DUBs), capable of removing ubiquitin (Ub) from protein substrates, are involved in numerous biological processes. The ubiquitin C-terminal hydrolases (UCHs) subfamily of DUBs consists of four members: UCH-L1, UCH-L3, UCH37 and BRCA1-associated protein-1 (BAP1). UCH-L1 possesses deubiquitinating activity and dimerization-dependent ubiquitin ligase activity, and functions as a mono-ubiquitin stabilizer; UCH-L3 does both deubiquitinating and deneddylating activity, except dimerization or ligase activity, and unlike UCH-L1, can interact with Lys48-linked Ub dimers to protect it from degradation and in the meanwhile to inhibit its hydrolase activity; UCH37 is responsible for the deubiquitinating activity in the 19S proteasome regulatory complex, and as indicated by the recent study, UCH37 is also associated with the human Ino80 chromatin-remodeling complex (hINO80) in the nucleus and can be activated via transient association of 19S regulatory particle- or proteasome-bound hRpn13 with hINO80; BAP1, binding to the wild-type BRCA1 RING finger domain, is regarded as a tumor suppressor, but for such suppressing activity, as demonstrated otherwise, both deubiquitinating activity and nucleus localization are required. There is growing evidence that UCH enzymes and human malignancies are closely correlated. Previous studies have shown that UCH enzymes play a crucial role in some signalings and cell-cycle regulation. In this review, we provided an insight into the relation between UCH enzymes and oncogenesis.     

Viral Bcl-2 homologs and their role in virus replication and associated diseases

Cellular Bcl-2 family proteins regulate a critical step in the mammalian programmed cell death pathway by modulating mitochondrial permeability and function. Bcl-2 family proteins are also encoded by several large DNA viruses, including all known gamma herpesviruses, adenoviruses, and several other unrelated viruses. Viral Bcl-2 proteins can prevent cell death but often escape cellular regulatory mechanisms that govern their cellular counterparts. By evading the "altruistic" suicide of infected cells, viruses can ensure replication and propagation in the infected host, but sometimes in surprising ways. Many human cancers and other disorders are associated with viruses that encode Bcl-2 homologs. Here we consider the available mechanistic data for viral compared to cellular Bcl-2 protein function along with relevance to the virus life cycle and human disease states.     

Lytic enzymes of Trichoderma and their role in protecting plants from fungal diseases

Lytic enzymes of mycoparasitic fungi of the genus Trichoderma, capable of suppressing several fungal phytopathogens that originate in air or soil, are reviewed. The topics analyzed include (1) regulation of production of chitinases, beta-1,3-glucanases, and proteases; (2) molecular and catalytic properties of purified enzymes; and (3) their in vitro ability to degrade cell walls and inhibit sporulation or germ-tube elongation in various phytopathogenic fungi. Among the results summarized are reports of cloning the expression of genes coding for certain lytic enzymes of Trichoderma spp. These genes are used for obtaining plant transgenes with increased resistance to fungal diseases and Trichoderma transformants that produce higher levels of one lytic enzyme (a chitinase or protease) and thereby exhibit a more pronounced ability to suppress phytopathogenic fungi.     

Circulation of respiratory viruses in Moscow and their role in acute respiratory diseases morbidity

Statistical data obtained during prolonged investigations on the structure of infective agents isolated from patients with acute respiratory diseases (ARD) in Moscow in 1989-1999 were analyzed. The study revealed that fluctuations of ARD morbidity rates were linked with the prevailing circulation of one or another type of the virus. The absence of the dominating role of influenza viruses was confirmed. The conclusion was made on the necessity of using, in addition to influenza vaccinal prophylaxis, chemoprophylactic interventions to maintain ARD morbidity on the acceptable level.     

Mycotoxins in Aspergillus

The toxigenicity of 392 strains ofAspergillus, representing 132 species and 19 varieties, was assessed on chicks and mice fed iso-caloric 50 % basal feed mixes of wheat and soybeans molded by these strains. On the basis of death numbers (3 or more of 6 on test), low weight gain of survivors, and low feed consumption over a 4-week period, 166 of the strains, representing 73 species and 9 varieties, were toxigenic. Ten species (A. alliaceus, A. avenaceus, A. clavato-flavus, A. janus, A. melleus, A. ochraceus, A. parasiticus, A. quercinus, A. sclerotiorum, andA. sulphureus) had strains that were markedly toxic to both animal types on one or both feeds; the other 63 species and 9 varieties had strains that were moderately to mildly toxic to one or both animal types on one or both feeds. In retests of some strains, toxigenicity varied between successive preparation of molded feed.This is a laboratory of the Northern Utilization Research and Development Division, Agricultural Research Service, United States Department of Agriculture.South Dakota Agricultural Experiment Station Journal Series No. 954.     

A review of non-cancer effects, especially circulatory and ocular diseases

There is a well-established association between high doses (>5 Gy) of ionizing radiation exposure and damage to the heart and coronary arteries, although only recently have studies with high-quality individual dosimetry been conducted that would enable quantification of this risk adjusting for concomitant chemotherapy. The association between lower dose exposures and late occurring circulatory disease has only recently begun to emerge in the Japanese atomic bomb survivors and in various occupationally exposed cohorts and is still controversial. Excess relative risks per unit dose in moderate- and low-dose epidemiological studies are somewhat variable, possibly a result of confounding and effect modification by well-known (but unobserved) risk factors. Radiation doses of 1 Gy or more are associated with increased risk of posterior subcapsular cataract. Accumulating evidence from the Japanese atomic bomb survivors, Chernobyl liquidators, US astronauts, and various other exposed groups suggests that cortical cataracts may also be associated with ionizing radiation, although there is little evidence that nuclear cataracts are radiogenic. The dose–response appears to be linear, although modest thresholds (of no more than about 0.6 Gy) cannot be ruled out. A variety of other non-malignant effects have been observed after moderate/low-dose exposure in various groups, in particular respiratory and digestive disease and central nervous system (and in particular neuro-cognitive) damage. However, because these are generally only observed in isolated groups, or because the evidence is excessively heterogeneous, these associations must be treated with caution.