Aurora B prevents chromosome arm separation defects by promoting telomere dispersion and disjunction

The segregation of centromeres and telomeres at mitosis is coordinated at multiple levels to prevent the formation of aneuploid cells, a phenotype frequently observed in cancer. Mitotic instability arises from chromosome segregation defects, giving rise to chromatin bridges at anaphase. Most of these defects are corrected before anaphase onset by a mechanism involving Aurora B kinase, a key regulator of mitosis in a wide range of organisms. Here, we describe a new role for Aurora B in telomere dispersion and disjunction during fission yeast mitosis. Telomere dispersion initiates in metaphase, whereas disjunction takes place in anaphase. Dispersion is promoted by the dissociation of Swi6/HP1 and cohesin Rad21 from telomeres, whereas disjunction occurs at anaphase after the phosphorylation of condensin subunit Cnd2. Strikingly, we demonstrate that deletion of Ccq1, a telomeric shelterin component, rescued cell death after Aurora inhibition by promoting the loading of condensin on chromosome arms. Our findings reveal an essential role for telomeres in chromosome arm segregation.     

Protrusive waves guide 3D cell migration along nanofibers

In vivo, cells migrate on complex three-dimensional (3D) fibrous matrices, which has made investigation of the key molecular and physical mechanisms that drive cell migration difficult. Using reductionist approaches based on 3D electrospun fibers, we report for various cell types that single-cell migration along fibronectin-coated nanofibers is associated with lateral actin-based waves. These cyclical waves have a fin-like shape and propagate up to several hundred micrometers from the cell body, extending the leading edge and promoting highly persistent directional movement. Cells generate these waves through balanced activation of the Rac1/N-WASP/Arp2/3 and Rho/formins pathways. The waves originate from one major adhesion site at leading end of the cell body, which is linked through actomyosin contractility to another site at the back of the cell, allowing force generation, matrix deformation and cell translocation. By combining experimental and modeling data, we demonstrate that cell migration in a fibrous environment requires the formation and propagation of dynamic, actin based fin-like protrusions.     

Advances in the synthesis and pharmacological activity of lupane-type triterpenoid saponins

Lupeol, betulin and betulinic acid are members of the so-called lupane-type triterpenoids. These natural products found worldwide in quite of lot of vegetables, fruits and plant species exhibit promising pharmacological activities including anti-inflammatory, anti-HIV and antitumor activities. Nevertheless, the poor pharmacokinetic properties of these cholesterol-like triterpenoids hampered further pharmaceutical developments. The synthesis of lupane-type saponins, i.e., sugar-derived lupanes, seems to be a good avenue to improve both their water solubility and pharmacological activity. The aims of this review are twofold: first, to describe the biological activity of naturally occurring lupane-type saponins, and second, report the different methodologies employed for the elaboration of glycosidic linkages at the C-3 and/or C-28 positions on the lupane core. The synthesis of both natural and unnatural lupane-type saponins is discussed with an emphasis on molecules exhibiting relevant biological activities.     

Use of biomarkers in clinical trials of Alzheimer disease: from concept to application

Research progress during the last decades has resulted in an unprecedented accumulation of knowledge regarding the molecular pathogenesis of Alzheimer disease (AD). These important achievements toward clarifying the mechanistic processes underlying AD are being translated into ongoing development of biomarkers and their use in clinical trials. AD biomarkers are biochemical and anatomical variables (e.g. cerebrospinal fluid, positron emission tomography, and structural MRI) that measure AD-related pathologic features (i.e. amyloid deposition and neurodegeneration) in vivo. Biomarkers are utilized as 'diagnostic biomarkers' and/or 'endpoint biomarkers' in symptomatic or disease-modifying clinical trials. Diagnostic biomarkers play an important role in population enrichment by refining selection criteria, stratifying populations, and increasing the statistical power of trials. Endpoint biomarkers may be used as outcome measures to monitor the rate of disease progression and detect treatment effects. AD biomarkers do not reach abnormal levels or peak simultaneously, but do so in a time-dependent order. The choice of biomarkers for a clinical trial must take into consideration the type of therapeutic intervention, the clinical stage of AD, and the time dependence of biomarker changes during disease progression. The combination of amyloid and neurodegeneration biomarkers is highly desirable since they capture different aspects of the disease. Clinical trials for every clinical stage of AD would benefit from quantification and standardization of biomarkers. However, this is still a work in progress.     

A general framework for modeling growth and division of mammalian cells

Background  

Modeling the cell-division cycle has been practiced for many years. As time has progressed, this work has gone from understanding the basic principles to addressing distinct biological problems, e.g., the nature of the restriction point, how checkpoints operate, the nonlinear dynamics of the cell cycle, the effect of localization, etc. Most models consist of coupled ordinary differential equations developed by the researchers, restricted to deal with the interactions of a limited number of molecules. In the future, cell-cycle modeling--and indeed all modeling of complex biologic processes--will increase in scope and detail.     

In vitro localization of the protein synthesis defect associated with experimental phenylketonuria

We have used a cell-free system derived from hamster brain to investigate protein synthesis during experimental phenylketonuria. In such a system the elongation inhibitor emetine impeded translation in extracts derived from both treated and control animals. On the other hand the initiation inhibitor aurintricarboxylic acid showed no effects on protein synthesis activity of treated hamsters, although it was severely inhibiting in controls. This suggests that initiation is the altered step in brain protein synthesis failure consecutive to phenylketonuria.Abbreviations ATA aurintricarboxylic acid - HPA hyperphenylalaninaemia (hyperphenylalaninaemic) - PHE phenylalanine - PKU phenylketonuria (phenylketonuric) - PR polyribosome     

Magnesium and Manganese Content of Halophilic Bacteria

Magnesium and manganese contents were measured by atomic absorption spectrophotometry in bacteria of several halophilic levels, in Vibrio costicola, a moderately halophilic eubacterium growing in 1 M NaCl, Halobacterium volcanii, a halophilic archaebacterium growing in 2.5 M NaCl, Halobacterium cutirubrum, an extremely halophilic archaebacterium growing in 4 M NaCl, and Escherichia coli, a nonhalophilic eubacterium growing in 0.17 M NaCl. Magnesium and manganese contents varied with the growth phase, being maximal at the early log phase. Magnesium and manganese molalities in cell water were shown to increase with the halophilic character of the logarithmically growing bacteria, from 30 mmol of Mg per kg of cell water and 0.37 mmol of Mn per kg of cell water for E. coli to 102 mmol of Mg per kg of cell water and 1.6 mmol of Mn per kg of cell water for H. cutirubrum. The intracellular concentrations of manganese were determined independently by a radioactive tracer technique in V. costicola and H. volcanii. The values obtained by ⁵⁴Mn loading represented about 70% of the values obtained by atomic absorption. The increase of magnesium and manganese contents associated with the halophilic character of the bacteria suggests that manganese and magnesium play a role in haloadaptation.     

Phylogeography of the Guinea multimammate mouse (Mastomys erythroleucus): a case study for Sahelian species in West Africa

Aim To investigate the phylogeographical structure of the Guinea multimammate mouse, Mastomys erythroleucus (Temminck, 1853), a widespread murid rodent in sub‐Saharan (Sahel and Sudan) savannas, for a better understanding of the impacts of geographical and historical factors on the evolutionary history of this species, in the context of the growing database of phylogeographical studies of African savanna mammal species. Location Sahel and Sudan savannas, Africa. Methods We sequenced the whole cytochrome b gene in 211 individuals from 59 localities distributed from Senegal to Ethiopia. Sequence data were analysed using both phylogenetic (several rooted tree‐construction methods, median‐joining networks) and population genetic methods (spatial analyses of molecular variance, mismatch distributions). Results Haplotypes were distributed into four major monophyletic groups corresponding to distinct geographical regions across a west–east axis. Diversification events were estimated to have occurred between 1.16 and 0.18 Ma. Main conclusions Vicariance events related to the fragmentation of savanna habitats during the Pleistocene era may explain the phylogeographical patterns observed. Genetic structure was consistent with a role of major Sahelian rivers as significant barriers to west–east dispersal. Recent demographic expansions probably occurred during arid phases of the Holocene with the southward expansion of savannas.