Phosphorylation and uphill intestinal transport of thiamine,in vitro

Riassunto L'impiego di tiamina-¹⁴C, con la tecnica dei sacchetti rovesciati di intestino di ratto, ha permesso di dimostrare che, durante il trasporto contro gradiente in vitro, la tiamina viene fosforilata dal tessuto intestinale. Gli inibitori metabolici e gli analoghi strutturali della tiamina che ne inibiscono la fosforilazione del pari ne riducono il trasporto netto. Ciò dimostra che il trasporto intestinale della tiamina è strettamente connesso con la sua fosforilazione.     

Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication

Early tumorigenesis is associated with the engagement of the DNA-damage checkpoint response (DDR). Cell proliferation and transformation induced by oncogene activation are restrained by cellular senescence. It is unclear whether DDR activation and oncogene-induced senescence (OIS) are causally linked. Here we show that senescence, triggered by the expression of an activated oncogene (H-RasV12) in normal human cells, is a consequence of the activation of a robust DDR. Experimental inactivation of DDR abrogates OIS and promotes cell transformation. DDR and OIS are established after a hyper-replicative phase occurring immediately after oncogene expression. Senescent cells arrest with partly replicated DNA and with DNA replication origins having fired multiple times. In vivo DNA labelling and molecular DNA combing reveal that oncogene activation leads to augmented numbers of active replicons and to alterations in DNA replication fork progression. We also show that oncogene expression does not trigger a DDR in the absence of DNA replication. Last, we show that oncogene activation is associated with DDR activation in a mouse model in vivo. We propose that OIS results from the enforcement of a DDR triggered by oncogene-induced DNA hyper-replication.     

Gravity modes as a way to distinguish between hydrogen- and helium-burning red giant stars

Red giants are evolved stars that have exhausted the supply of hydrogen in their cores and instead burn hydrogen in a surrounding shell. Once a red giant is sufficiently evolved, the helium in the core also undergoes fusion. Outstanding issues in our understanding of red giants include uncertainties in the amount of mass lost at the surface before helium ignition and the amount of internal mixing from rotation and other processes. Progress is hampered by our inability to distinguish between red giants burning helium in the core and those still only burning hydrogen in a shell. Asteroseismology offers a way forward, being a powerful tool for probing the internal structures of stars using their natural oscillation frequencies. Here we report observations of gravity-mode period spacings in red giants that permit a distinction between evolutionary stages to be made. We use high-precision photometry obtained by the Kepler spacecraft over more than a year to measure oscillations in several hundred red giants. We find many stars whose dipole modes show sequences with approximately regular period spacings. These stars fall into two clear groups, allowing us to distinguish unambiguously between hydrogen-shell-burning stars (period spacing mostly ～ 50 seconds) and those that are also burning helium (period spacing ～ 100 to 300 seconds).     

FINDCLUS: Fuzzy INdividual Differences CLUStering

ADditive CLUStering (ADCLUS) is a tool for overlapping clustering of two-way proximity matrices (objects?×?objects). In Simple Additive Fuzzy Clustering (SAFC), a variant of ADCLUS is introduced providing a fuzzy partition of the objects, that is the objects belong to the clusters with the so-called membership degrees ranging from zero (complete non-membership) to one (complete membership). INDCLUS (INdividual Differences CLUStering) is a generalization of ADCLUS for handling three-way proximity arrays (objects?×?objects?×?subjects). Here, we propose a fuzzified alternative to INDCLUS capable to offer a fuzzy partition of the objects by generalizing in a three-way context the idea behind SAFC. This new model is called Fuzzy INdividual Differences CLUStering (FINDCLUS). An algorithm is provided for fitting the FINDCLUS model to the data. Finally, the results of a simulation experiment and some applications to synthetic and real data are discussed.     

A Fuzzy Clustering Model for Multivariate Spatial Time Series

Clustering of multivariate spatial-time series should consider: 1) the spatial nature of the objects to be clustered; 2) the characteristics of the feature space, namely the space of multivariate time trajectories; 3) the uncertainty associated to the assignment of a spatial unit to a given cluster on the basis of the above complex features. The last aspect is dealt with by using the Fuzzy C-Means objective function, based on appropriate measures of dissimilarity between time trajectories, by distinguishing the cross-sectional and longitudinal aspects of the trajectories. In order to take into account the spatial nature of the statistical units, a spatial penalization term is added to the above function, depending on a suitable spatial proximity/ contiguity matrix. A tuning coefficient takes care of the balance between, on one side, discriminating according to the pattern of the time trajectories and, on the other side, ensuring an approximate spatial homogeneity of the clusters. A technique for determining an optimal value of this coefficient is proposed, based on an appropriate spatial autocorrelation measure. Finally, the proposed models are applied to the classification of the Italian provinces, on the basis of the observed dynamics of some socio-economical indicators.     

Elevation of serum xanthine oxidase following halothane anesthesia in the rat

Summary Halothane anesthesia was found to be hepatotoxic in the rat, as demonstrated by a significant elevation of serum xanthine oxidase (SXO) level. SXO appeared to be a more sensitive marker of liver damage than serum, glutamic oxalacetic transaminsa. SXO was found to be elevated also following exposure to relative hypoxia.     

PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR

Loss of the promyelocytic leukaemia (PML) tumour suppressor has been observed in several human cancers. The tumour-suppressive function of PML has been attributed to its ability to induce growth arrest, cellular senescence and apoptosis. Here we identify PML as a critical inhibitor of neoangiogenesis (the formation of new blood vessels) in vivo, in both ischaemic and neoplastic conditions, through the control of protein translation. We demonstrate that in hypoxic conditions PML acts as a negative regulator of the synthesis rate of hypoxia-inducible factor 1alpha (HIF-1alpha) by repressing mammalian target of rapamycin (mTOR). PML physically interacts with mTOR and negatively regulates its association with the small GTPase Rheb by favouring mTOR nuclear accumulation. Notably, Pml-/- cells and tumours display higher sensitivity both in vitro and in vivo to growth inhibition by rapamycin, and lack of PML inversely correlates with phosphorylation of ribosomal protein S6 and tumour angiogenesis in mouse and human tumours. Thus, our findings identify PML as a novel suppressor of mTOR and neoangiogenesis.     

From in vivo to in silico biology and back

The massive acquisition of data in molecular and cellular biology has led to the renaissance of an old topic: simulations of biological systems. Simulations, increasingly paired with experiments, are being successfully and routinely used by computational biologists to understand and predict the quantitative behaviour of complex systems, and to drive new experiments. Nevertheless, many experimentalists still consider simulations an esoteric discipline only for initiates. Suspicion towards simulations should dissipate as the limitations and advantages of their application are better appreciated, opening the door to their permanent adoption in everyday research.