Senescence and apoptosis in yeast mother cell-specific aging and in higher cells: a short review

It is our intention to give the reader a short overview of the relationship between apoptosis and senescence in yeast mother cell-specific aging. We are studying yeast as an aging model because we want to learn something of the basic biology of senescence and apoptosis even from a unicellular eukaryotic model system, using its unrivalled ease of genetic analysis. Consequently, we will discuss also some aspects of apoptosis in metazoa and the relevance of yeast apoptosis and aging research for cellular (Hayflick type) and organismic aging of multicellular higher organisms. In particular, we will discuss the occurrence and relevance of apoptotic phenotypes for the aging process. We want to ask the question whether apoptosis (or parts of the apoptotic process) are a possible cause of aging or vice versa and want to investigate the role of the cellular stress response system in both of these processes. Studying the current literature, it appears that little is known for sure in this field and our review will therefore be, for a large part, more like a memorandum or a program for future research.     

Impaired Temperature Stress Response of a Streptococcus thermophilus deoD Mutant

An insertional deoD mutant of Streptococcus thermophilus strain SFi39 had a reduced growth rate at 20°C and an enhanced survival capacity to heat shock compared to the wild type, indicating that the deoD product is involved in temperature shock adaptation. We report evidence that ppGpp is implicated in this dual response.     

Synthesis and biological activity of new 1,4-benzodioxan-arylpiperazine derivatives. Further validation of a pharmacophore model for alpha(1)-adrenoceptor antagonists.

A series of WB4101 (1)-related benzodioxanes (2-17) have been synthesized by replacing the phenoxyethyl moiety of 1 with a N-alkyl piperazine bearing a cyclic substituent (a substituted or unsubstituted phenyl group, a pyridine or pyridazinone ring, a furoyl moiety) at the second nitrogen atom. The binding profile of these compounds has been assessed by radioligand receptor binding assay at alpha(1)- and alpha(2)-adrenoceptors, in comparison to prazosin and rauwolscine, respectively. Moreover, structure-activity relationships have been derived for compounds 2-17 based on their fitting to a pharmacophore model for alpha(1)-adrenoceptor antagonists recently proposed by our research group. In a parallel way, the same compounds have been used to further test the predictive power and statistical significance of the model itself. The accuracy of the results obtained also in this case revealed the robustness of the calculated pharmacophore model and led to the identification of the molecular structural moieties which are thought to contribute to the biological activity.     

Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer

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Thermodynamic Modeling of Internal Equilibria Involved in the Activation of Trypsinogen

Abstract

The effect of activating dipeptides, sequentially homologous to the Ile 16-Val 17 N-terminus of bovine β-trypsin (β-trypsin), on equilibria involved in the binding of strong ligands (i.e., n-butylamine, the bovine basic pancreatic trypsin inhibitor (Kunitz-type inhibitor; BPTI) and the porcine pancreatic secretory trypsin inhibitor (Kazal-type inhibitor, type I; PSTI)) to bovine trypsinogen (trypsinogen) was investigated at pH 5.5 (I = 0.1 M) and T = 21.0 ± 0.5°C; under the same experimental conditions, thermodynamics for the binding of strong ligands to β-trypsin was also obtained. The equilibria involved in the binding of activating dipeptides and/or inhibitors to β-trypsin and to its zymogen are described according to an induced-fit formalism, taking into account ligand-linked interaction(s) between different functional and structural domains of the (pro)enzyme possibly involved in the trypsinogen-to-β-trypsin activation pathway. The analysis of data is focussed on parameters describing interactions between the so-called Ile-Val pocket (where the Ile16-Val17/V-terminus of β-trypsin or activating dipeptides bind) and the primary and/or secondary recognition subsite(s) (where strong ligands associate) present in the (pro)enzyme. Such an analysis allows to dissect the contributions due to the primary recognition subsite, where small mono-functional ligands (e.g., n-butylamine) bind, from those of the secondary subsite(s), which are additional recognition clefts for macromolecular inhibitors (e.g., BPTI and PSTI).     

Molecular basis of α-thalassemia in Sicily

To evaluate the allelic frequency and genetic diversity of α-thalassemia defects in Sicily, both epidemiological and patient-oriented studies were carried out. For the epidemiological study, phenotypic data were collected on more than 1000 Sicilian individuals. Among them, 427 were explored at the molecular level for nine α-thalassemic variants known to be common in the Mediterranean region. Our data reveal an allele frequency of 4.1% for α⁺-thalassemia matching that of β-thalassemia in this region. The presence of α°-thalassemia (––^MEDI and ––^CAL) was observed only in the group of referred patients. Newly acquired nucleotide sequence data on the deletional breakpoint of ––^CAL allowed us to design a simple PCR-based procedure for exploring this allele. The data also provide additional information concerning the genetic mechanisms involved in such large deletions. Received: 8 August 1996 / Revised: 16 October 1996