Path integration and the neural basis of the 'cognitive map'

The hippocampal formation can encode relative spatial location, without reference to external cues, by the integration of linear and angular self-motion (path integration). Theoretical studies, in conjunction with recent empirical discoveries, suggest that the medial entorhinal cortex (MEC) might perform some of the essential underlying computations by means of a unique, periodic synaptic matrix that could be self-organized in early development through a simple, symmetry-breaking operation. The scale at which space is represented increases systematically along the dorsoventral axis in both the hippocampus and the MEC, apparently because of systematic variation in the gain of a movement-speed signal. Convergence of spatially periodic input at multiple scales, from so-called grid cells in the entorhinal cortex, might result in non-periodic spatial firing patterns (place fields) in the hippocampus.     

Age-related changes in endothelial nitric oxide synthase phosphorylation and nitric oxide dependent vasodilation: evidence for a novel mechanism involving sphingomyelinase and ceramide-activated phosphatase 2A

Aging is the single most important risk factor for cardiovascular diseases (CVD), which are the leading cause of morbidity and mortality in the elderly. The underlying etiologies that elevate CVD risk are unknown, but increased vessel rigidity appears to be a major hallmark of cardiovascular aging. We hypothesized that post-translational signaling pathways become disrupted with age and adversely affect endothelial nitric oxide synthase (eNOS) activity and endothelial-derived nitric oxide (NO) production. Using arterial vessels and isolated endothelia from old (33-month) vs. young (3-month) F344XBrN rats, we show a loss of vasomotor function with age that is attributable to a decline in eNOS activity and NO bioavailability. An altered eNOS phosphorylation pattern consistent with its inactivation was observed: phosphorylation at the inhibitory threonine 494 site increased while phosphorylation at the activating serine 1176 site declined by 50%. Loss of phosphorylation on serine 1176 was related to higher ceramide-activated protein phosphatase 2 A activity, which was driven by a 125% increase in ceramide in aged endothelia. Elevated ceramide levels were attributable to chronic activation of neutral sphingomyelinases without a concomitant increase in ceramidase activity. This imbalance may stem from an observed 33% decline in endothelial glutathione (GSH) levels, a loss known to differentially induce neutral sphingomyelinases. Pretreating aged vessel rings with the neutral sphingomyelinase inhibitor, GW4869, significantly reversed the age-dependent loss of vasomotor function. Taken together, these results suggest a novel mechanism that at least partly explains the persistent loss of eNOS activity and endothelial-derived NO availability in aging conduit arteries.     

Neural processing of auditory looming in the human brain

Acoustic intensity change, along with interaural, spectral, and reverberation information, is an important cue for the perception of auditory motion. Approaching sound sources produce increases in intensity, and receding sound sources produce corresponding decreases. Human listeners typically overestimate increasing compared to equivalent decreasing sound intensity and underestimate the time to contact of approaching sound sources. These characteristics could provide a selective advantage by increasing the margin of safety for response to looming objects. Here, we used dynamic intensity and functional magnetic resonance imaging to examine the neural underpinnings of the perceptual priority for rising intensity. We found that, consistent with activation by horizontal and vertical auditory apparent motion paradigms, rising and falling intensity activated the right temporal plane more than constant intensity. Rising compared to falling intensity activated a distributed neural network subserving space recognition, auditory motion perception, and attention and comprising the superior temporal sulci and the middle temporal gyri, the right temporoparietal junction, the right motor and premotor cortices, the left cerebellar cortex, and a circumscribed region in the midbrain. This anisotropic processing of acoustic intensity change may reflect the salience of rising intensity produced by looming sources in natural environments.     

Impact of preanalytical handling and timing for peripheral blood mononuclear cells isolation and RNA studies: the experience of the Interinstitutional Multidisciplinary BioBank (BioBIM)

Multicenter studies and biobanking projects require blood transportation from the participating center to a central collection or diagnostic laboratory. The impact of time delays between venous blood collection and peripheral blood mononuclear cells (PBMC) isolation prior to RNA extraction may affect the quality and quantity of isolated nucleic acids for genomic applications. Thus, standard operating procedure (SOP) optimization for the treatment of biological samples before RNA extraction is crucial in a biological repository. In order to define SOPs for whole blood preservation prior to RNA extraction, we sought to determine whether different blood storage times (0, 3, 6, 10, 24, and 30 hours) prior to PBMCs isolation and storage at -80°C, could affect the quality and quantity of extracted RNA. After spectrophotometric quantification, the quality and integrity of RNA were assessed by agarose gel electrophoresis, RNA integrity number and real time-PCR (RT-PCR).?Across the different time points we did not observe significant differences within the first 24 hours of blood storage at room temperature, while a significant loss in RNA yield and integrity was detected between 24 and 30 hours. We conclude that time delays before PBMCs isolation prior to RNA extraction may have a significant impact on downstream molecular biological applications.     

Temperature preferences of bacteria isolated from seawater collected in Kandalaksha Bay,White Sea,Russia

Fifty-two bacteria were isolated from seawater collected in Kandalaksha Bay, White Sea, Russia, and classified by 16S rDNA sequencing. Most of the strains belonged to ubiquitous microorganisms. Pseudomonas was the most abundant genus (21 strains), including species of P. fluorescens, P. putida and P. syringae. Serratia was also common (10 strains) with species S. plymuthica and S. proteamaculans. Sphingobacterium, Flavobacterium and Pantoea were less represented (5, 3 and 2 strains, respectively). The only typical bacterium of marine Arctic regions was Shewanella baltica. The strains were tested for their optimal growth temperature in the range 0–45°C. The majority appeared to be psychrotolerant (42%) or mesophilic-psychrotolerant (40%). In addition, one strain (Bacillus pumilus) showed a rather narrow mesophilic profile. No true psychrophilic bacteria were found. Most of the strains showed a classical curve with fast growth decrease above the optimum; some others displayed uncommon flat curves with scarce differences between maximum and minimum of growth in a wide range of temperatures. Moreover, few strains presented an unusual profile being, in relation to the optimum, more tolerant to high rather than low temperatures. Preferences of the Kandalaksha Bay strains are generally different from those reported in literature for the same species: optima were at lower temperatures and, sometimes, ranges were broader showing increased eurythermism. This could indicate adaptation to the wide temperature variations recorded in this peculiar environment.     

Arabidopsis AtNek2 Kinase is Essential and Associates with Microtubules

NIMA-related kinases (Neks) are a large family of serine/threonine kinases that have been linked to cell-cycle regulation in fungi and mammals. Large families of NIMA-related kinases are also conserved in plants. We demonstrate that AtNek2, a member of the NIMA-related kinase family in Arabidopsis, is a gene fundamental for plant survival and its down-regulation has a pleiotropic effect on leaf cell morphogenesis and plant development. Intracellular localization of YFP::AtNek2 showed that AtNek2 proteins co-distribute with the microtubular cytoskeleton. As a microtubular-associated protein AtNek2 might influence the dynamics of microtubules and consequently cell morphogenesis. This is supported by the observation that misexpression of AtNek2 in RNAi mutants leads to a distorted organization of cells.     

Effects of doxorubicin cancer therapy on autophagy and the ubiquitin-proteasome system in long-term cultured adult rat cardiomyocytes

The clinical use of anthracyclines in cancer therapy is limited by dose-dependent cardiotoxicity that involves cardiomyocyte injury and death. We have tested the hypothesis that anthracyclines affect protein degradation pathways in adult cardiomyocytes. To this aim, we assessed the effects of doxorubicin (Doxo) on apoptosis, autophagy and the proteasome/ubiquitin system in long-term cultured adult rat cardiomyocytes. Accumulation of poly-ubiquitinated proteins, increase of cathepsin-D-positive lysosomes and myofibrillar degradation were observed in Doxo-treated cardiomyocytes. Chymotrypsin-like activity of the proteasome was initially increased and then inhibited by Doxo over a time-course of 48 h. Proteasome 20S proteins were down-regulated by higher doses of Doxo. The expression of MURF-1, an ubiquitin-ligase specifically targeting myofibrillar proteins, was suppressed by Doxo at all concentrations measured. Microtubule-associated protein?1 light chain 3B (LC3)-positive punctae and both LC3-I and -II proteins were induced by Doxo in a dose-dependent manner, as confirmed by using lentiviral expression of green fluorescence protein bound to LC3 and live imaging. The lysosomotropic drug chloroquine led to autophagosome accumulation, which increased with concomitant Doxo treatment indicating enhanced autophagic flux. We conclude that Doxo causes a downregulation of the protein degradation machinery of cardiomyocytes with a resulting accumulation of poly-ubiquitinated proteins and autophagosomes. Although autophagy is initially stimulated as a compensatory response to cytotoxic stress, it is followed by apoptosis and necrosis at higher doses and longer exposure times. This mechanism might contribute to the late cardiotoxicity of anthracyclines by accelerated aging of the postmitotic adult cardiomyocytes and to the susceptibility of the aging heart to anthracycline cancer therapy.     

Deregulation of signalling pathways in prognostic subtypes of hepatocellular carcinoma: Novel insights from interspecies comparison

Hepatocellular carcinoma is a frequent and fatal disease. Recent researches on rodent models and human hepatocarcinogenesis contributed to unravel the molecular mechanisms of hepatocellular carcinoma dedifferentiation and progression, and allowed the discovery of several alterations underlying the deregulation of cell cycle and signalling pathways. This review provides an interpretive analysis of the results of these studies. Mounting evidence emphasises the role of up-regulation of RAS/ERK, PI3K/AKT, IKK/NF-kB, WNT, TGF-β, NOTCH, Hedgehog, and Hippo signalling pathways as well as of aberrant proteasomal activity in hepatocarcinogenesis. Signalling deregulation often occurs in preneoplastic stages of rodent and human hepatocarcinogenesis and progressively increases in carcinomas, being most pronounced in more aggressive tumours. Numerous changes in signalling cascades are involved in the deregulation of carbohydrate, lipid, and methionine metabolism, which play a role in the maintenance of the transformed phenotype. Recent studies on the role of microRNAs in signalling deregulation, and on the interplay between signalling pathways led to crucial achievements in the knowledge of the network of signalling cascades, essential for the development of adjuvant therapies of liver cancer. Furthermore, the analysis of the mechanisms involved in signalling deregulation allowed the identification of numerous putative prognostic markers and novel therapeutic targets of specific hepatocellular carcinoma subtypes associated with different biologic and clinical features. This is of prime importance for the selection of patient subgroups that are most likely to obtain clinical benefit and, hence, for successful development of targeted therapies for liver cancer.     

Does genetic population structure of Ambrosina bassii L. (Araceae,Ambrosineae) attest a post-Messinian land-bridge between Sicily and Africa?

Aim of the present work is the analysis (through the study of enzyme polymorphism) of Sicilian and African (Tunisian) populations of Ambrosina bassii, a small perennial endemic to the Central-Western Mediterranean basin, in order to verify if the complex geological history of this part of the Mediterranean area left its mark in the present-day genetic structure of this taxon. Starch gel allozyme electrophoresis of seven putative loci of A. bassii was employed to estimate genetic diversity, genetic structure and gene flow. Populations from Sicily, Tunisia and Sardinia (as outgroup) were sampled. Results show that Sicily populations have 4 private alleles, Sardinia 3, Tunisia just one. One allele is private to both Sardinia and Tunisia, another one to Sardinia and Sicily. Even if there are no alleles private to Sicily and Tunisia, “cluster analysis” (based on Nei's genetic distances), “non-metric multidimensional scaling” (computed on the basis of a matrix with F_ST values between populations) and Bayesian analysis point out a clear isolation of Sardinian populations, and a greater similarity between Sicilian and Tunisian populations compared to Sardinian ones. The strong genetic affinity between populations from Sicily and Tunisia, considering the very low dispersal ability of the species, gives evidence of a recent continuity between the populations as well as between the two areas. Considering also the estimates of divergence times, a post-Messinian terrestrial connection between the two landmasses can be hypothesized.