Fungal toxins as a parasitic factor responsible for the establishment of fungal infections

Although the mechanism of fungal infections, particularly that of opportunistic fungus infections, has been studied extensively, much still remains to be clarified. As is the case for certain bacterial infections, it has long been assumed by numerous investigators that some toxins, enzymes and other metabolites produced in vitro as well as in vivo by pathogenic fungi or their cellular constituents might be responsible for the establishment of fungal infections. However, there are very few papers which deal with isolation and/or characterization of pathogenic fungus-derived toxins, particularly those of high molecular weight, to sufficiently meet various criteria for toxins including etiopathological ability. Likewise, it has been speculated that certain enzymes produced by pathogenic fungi are related to the pathogenesis of infections with the fungi implicated, but no direct evidence has been provided.It is commonly held by researchers concerned with medical mycology that the lowering of specific and/or nonspecific resistance of a host to pathogenic fungi is a prerequisite for the establishment of infections, particularly opportunistic infections. However, it is also accepted that if a given fungus possesses no parasite factors (e.g. toxigenicity, invasiveness and others), it would be unable to initiate infection even when the host is in a severe immunodeficient state. This is supported by our recent studies working with Saccharomyces cerevisiae and some other so-called nonpathogenic yeasts (unpublished data). Based on these considerations, the author and his co-workers have attempted to isolate several high and low molecular weight toxins in a pure state from virulent strains of Candida albicans and Aspergillus fumigatus as opportunist. Studies have also been made on the etiopathological roles of some successfully isolated toxins in infections with the fungi implicated (46).In addition to our experimental results, general concepts in fungal toxins, particularly those related to such toxins as isolated in our laboratory are outlined. Since opportunistic fungus infections have created a global problem because of their world-wide prevalence, a sharp demarcation between the so-called pathogenic and nonpathogenic fungi has become vague. Despite this situation, two terms are conventionally used throughout this paper.The author thanks Drs. H. Yamaguchi and K. Uchida, Y. Yamamoto, T. Hiratani, and Y. Nozu for their collaboration during these studies.     

Noncanonical Transforming Growth Factor β (TGFβ) Signaling in Cranial Neural Crest Cells Causes Tongue Muscle Developmental Defects

Microglossia is a congenital birth defect in humans and adversely impacts quality of life. In vertebrates, tongue muscle derives from the cranial mesoderm, whereas tendons and connective tissues in the craniofacial region originate from cranial neural crest (CNC) cells. Loss of transforming growth factor β (TGFβ) type II receptor in CNC cells in mice (Tgfbr2^fl/fl;Wnt1-Cre) causes microglossia due to a failure of cell-cell communication between cranial mesoderm and CNC cells during tongue development. However, it is still unclear how TGFβ signaling in CNC cells regulates the fate of mesoderm-derived myoblasts during tongue development. Here we show that activation of the cytoplasmic and nuclear tyrosine kinase 1 (ABL1) cascade in Tgfbr2^fl/fl;Wnt1-Cre mice results in a failure of CNC-derived cell differentiation followed by a disruption of TGFβ-mediated induction of growth factors and reduction of myogenic cell proliferation and differentiation activities. Among the affected growth factors, the addition of fibroblast growth factor 4 (FGF4) and neutralizing antibody for follistatin (FST; an antagonist of bone morphogenetic protein (BMP)) could most efficiently restore cell proliferation, differentiation, and organization of muscle cells in the tongue of Tgfbr2^fl/fl;Wnt1-Cre mice. Thus, our data indicate that CNC-derived fibroblasts regulate the fate of mesoderm-derived myoblasts through TGFβ-mediated regulation of FGF and BMP signaling during tongue development.     

Association between light exposure at night and manic symptoms in bipolar disorder: cross-sectional analysis of the APPLE cohort

ABSTRACT

Previous studies have found that keeping the room dark at night was associated with a decrease in manic symptoms for patients with bipolar disorder (BD). However, the association between light at night of real-life conditions and manic symptoms is unclear. We investigated the association between bedroom light exposure at night and manic symptoms in BD patients. One-hundred and eighty-four outpatients with BD participated in this cross-sectional study. The average light intensity at night during sleep was evaluated using a portable photometer for seven consecutive nights. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS), and scores ≥5 were treated as a “hypomanic state.” The median (interquartile range) YMRS score was 2.0 (0–5.0), and 52 (28.2%) participants were in a hypomanic state. The prevalence of a hypomanic state was significantly higher in the participants with an average light intensity at night exposure of ≥3 lux than in those with <3 lux (36.7% versus 21.9%; P = .02). In multivariable logistic regression analysis adjusted for BD type, depressive symptoms, sleep duration, and daytime physical activity, the odds ratio (OR) for a hypomanic state was significantly higher for the participants with an average light intensity at night exposure of ≥3 lux than for those with <3 lux (OR: 2.15, 95% confidence interval: 1.09–4.22, P = .02). This association remained significant at the cutoff value of YMRS score ≥6 (OR: 2.51, 95% confidence interval: 1.15–5.46; P = .02). The findings of this study indicate bedroom light exposure at night is significantly associated with manic symptoms in BD patients. Although the results of this cross-sectional investigation do not necessarily imply causality, they may serve to inform beneficial nonpharmacological intervention and personalized treatment of BD patients.     

Stimulation of thiamine diphosphate activity by ascorbic acid in rat brain microsomes

The effect of ascorbic acid on microsomal thiamine diphosphate activity in rat brain was examined. Ascorbic acid at 0.02–0.1 mM increased the thiamine diphosphate activity by 20–600% and produced a significant amount of lipid peroxide, which was measured with thiobarbiturate under the same conditions as the enzyme. A lag period of about 10 min was observed in the process of stimulation of enzyme activity by ascorbic acid. The stimulation of enzyme activity and the lipid peroxidation induced by ascorbic acid were blocked by metal-binding compounds (EDTA, α,α′-dipyridyl, o-phenanthroline) and an antioxidant (N,N′-diphenyl p-phenylenediamine). GSH significantly enhanced the stimulation of enzyme activity and formation of lipid peroxide by 0.02–0.05 mM ascorbic acid. The effect of GSH was due in part to maintenance of the concentration of ascorbic acid in the medium, since GSH could convert dehydroascorbic acid, an oxidized form of ascorbic acid, to ascorbic acid.     

Microorganism Capable of Decomposing N-Acetylglucosaminyl Ribitol Teichoic Acid of Staphylococcus aureus

Enzyme(s) capable of decomposing N-acetylglucosaminyl ribitol teichoic acid prepared from the cell wall of Staphylococcus aureus FDA 209 P was obtained from the culture supernatant of a gram-negative, rod-shaped, spore-forming soil bacterium. Properties of the bacterium were very similar to those of Bacillus circulans.     

High-resolution crystal structures of transient intermediates in the phytochrome photocycle

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Increased sensitivity to phagocytosis of Staphylococcus E-46 after growth in artificial media

Staphylococcus E-46, which exhibits high virulence in mice mainly due to resistance to phagocytosis, gradually lost its virulence during growth in artificial media [Heart-Infusion (HI) slants]. Staphylococcus E-46 is coagulase-negative and DNase-positive, and has a capsule-like structure, and the less-virulent derivative (LVD) strain seemed not to be changed in this respect. The bacteria which had been exposed to HI slants for more than one year (= LVD strain) became more sensitive to phagocytosis by mouse peritoneal macrophages than bacteria which were kept in a lyophilized state. The chemiluminescent response of macrophages to the LVD strain was remarkably higher than that to the original Staphylococcus E-46. When the LVD or the sera for opsonization were heated, the chemiluminescence to the LVD was as low as that to the original Staphylococcus E-46. Polyacrylamide gel electrophoresis of sonication-released membrane protein from the LVD strain showed a unique band with a molecular weight of about 40,000. The factor concerned with the virulence of Staphylococcus E-46 is discussed based on these results.     

Artificial cationic peptides that increase nuclease resistance of siRNA without disturbing RNAi activity

Properties of cationic peptides bearing amino or guanidino groups with various side chain lengths that bind to double stranded RNAs (dsRNAs) were investigated. Peptides with shorter side chain lengths effectively bound to dsRNAs (12mers) increasing their thermal stability. NMR measurements suggested that the cationic peptide binds to the inner side of the major groove of dsRNA. These peptides also increased the thermal stability of siRNA and effectively protected from RNase A digestion. On the other hand, both peptides containing amino groups and guanidine groups did not disturb RNAi activity.