The quest for new antibiotics, especially those with activity against Gram-negative bacteria, is urgent; however, very few new antibiotics have been marketed in the last 40 years, with this limited number falling into only four new structural classes. Several nucleoside natural product antibiotics target bacterial translocase MraY, involved in the lipid-linked cycle of peptidoglycan biosynthesis, and fungal chitin synthase. Biosynthetic studies on the nikkomycin, caprazamycin and pacidamycin/mureidomycin families are also reviewed.
An essential feature of the organization and function of the vertebrate and insect olfactory systems is the generation of a variety of olfactory receptor neurons (ORNs) that have different specificities in regard to both odorant receptor expression and axonal targeting. Yet the underlying mechanisms that generate this neuronal diversity remain elusive. Here we demonstrate that the Notch signal is involved in the diversification of ORNs in Drosophila melanogaster. A systematic clonal analysis showed that a cluster of ORNs housed in each sensillum were differentiated into two classes, depending on the level of Notch activity in their sibling precursors. Notably, ORNs of different classes segregated their axonal projections into distinct domains in the antennal lobes. In addition, both the odorant receptor expression and the axonal targeting of ORNs were specified according to their Notch-mediated identities. Thus, Notch signaling contributes to the diversification of ORNs, thereby regulating multiple developmental events that establish the olfactory map in Drosophila.
The biosynthesis of peptidoglycan is essential for all bacteria and has no counterpart in eukaryotic cells. It is one of the prime targets for antibiotic chemotherapy, especially phospho-MurNAc-pentapeptide translocase (translocase I) is a fascinating target in which there is no commercial antibiotic. In this review we will describe three nucleoside translocase I inhibitors, mureidomycin, tunicamycin and liposidomycin.
At the last step of metamorphosis in Drosophila, the wing epidermal cells are removed by programmed cell death during the wing spreading behavior after eclosion. The cell death was accompanied by DNA fragmentation demonstrated by the TUNEL assay. Transmission electron microscopy revealed that this cell death exhibited extensive vacuoles, indicative of autophagy. Ectopic expression of an anti-apoptotic gene, p35, inhibited the cell death, indicating the involvement of caspases. Neck ligation and hemolymph injection experiments demonstrated that the cell death is triggered by a hormonal factor secreted just after eclosion. The timing of the hormonal release implies that the hormone to trigger the death might be the insect tanning hormone, bursicon. This was supported by evidence that wing cell death was inhibited by a mutation of rickets, which encodes a G-protein coupled receptor in the glycoprotein hormone family that is a putative bursicon receptor. Furthermore, stimulation of components downstream of bursicon, such as a membrane permeant analog of cAMP, or ectopic expression of constitutively active forms of G proteins or PKA, induced precocious death. Conversely, cell death was inhibited in wing clones lacking G protein or PKA function. Thus, activation of the cAMP/PKA signaling pathway is required for transduction of the hormonal signal that induces wing epidermal cell death after eclosion.
Background: For the establishment of functional neural circuits that support a wide range of animal behaviors, initial circuits formed in early development have to be reorganized. One way to achieve this is local remodeling of the circuitry hardwiring. To genetically investigate the underlying mechanisms of this remodeling, one model system employs a major group of Drosophila multidendritic sensory neurons -the dendritic arborization (da) neurons -which exhibit dramatic dendritic pruning and subsequent growth during metamorphosis. The 15 da neurons are identified in each larval abdominal hemisegment and are classified into four categories -classes I to IV -in order of increasing size of their receptive fields and/or arbor complexity at the mature larval stage. Our knowledge regarding the anatomy and developmental basis of adult da neurons is still fragmentary.
Propeptin, an inhibitor of the prolyl endopeptidase isolated from the mycelium of Microbispora sp. SNA-115, is an atypical cyclic peptide antibiotic. It was purified by column chromatographies on silica gel and Sephadex LH-20 and high performance liquid chromatography using an ODS column. Propeptin has the molecular formula of C113H142N26O27 and consists of nineteen amino acids. Propeptin inhibited prolyl endopeptidase of the genus Flavobacterium competitively when Z-Gly-Pro-/?NA was used as a substrate. The inhibitor constant (Ki) was 0.70 mm.
Dynamics of insulin and glucagon secretion were investigated by using a new model of spontaneous diabetes rats produced by the repetition of selective breeding in our laboratories. The perfusion experiments of the pancreas showed that the early phase of insulin secretion to continuous stimulation with glucose was specifically impaired, although the response of the early phase to arginine was preserved. The glucose-induced insulin secretion in the nineth generation (F8) which had a more remarkably impaired glucose tolerance was more reduced than in the sixth generation (F5). No significant difference of glucagon secretion in response to arginine or norepinephrine was noted between the diabetes rats and control ones. The present data indicate that the defective insulin secretion is a primary derangement in a diabetic state of the spontaneous diabetes rat. This defect in the early phase of glucose-induced insulin secretion suggests the specific impairment of the recognition of glucose by the pancreatic beta-cells. The spontaneous diabetes rats are very useful as a model of disease for investigating pathophysiology of non-insulin dependent diabetes mellitus.
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