Extra-visual functional and structural connection abnormalities in Leber's hereditary optic neuropathy

We assessed abnormalities within the principal brain resting state networks (RSNs) in patients with Leber's hereditary optic neuropathy (LHON) to define whether functional abnormalities in this disease are limited to the visual system or, conversely, tend to be more diffuse. We also defined the structural substrates of fMRI changes using a connectivity-based analysis of diffusion tensor (DT) MRI data. Neuro-ophthalmologic assessment, DT MRI and RS fMRI data were acquired from 13 LHON patients and 13 healthy controls. RS fMRI data were analyzed using independent component analysis and SPM5. A DT MRI connectivity-based parcellation analysis was performed using the primary visual and auditory cortices, bilaterally, as seed regions. Compared to controls, LHON patients had a significant increase of RS fluctuations in the primary visual and auditory cortices, bilaterally. They also showed decreased RS fluctuations in the right lateral occipital cortex and right temporal occipital fusiform cortex. Abnormalities of RS fluctuations were correlated significantly with retinal damage and disease duration. The DT MRI connectivity-based parcellation identified a higher number of clusters in the right auditory cortex in LHON vs. controls. Differences of cluster-centroid profiles were found between the two groups for all the four seeds analyzed. For three of these areas, a correspondence was found between abnormalities of functional and structural connectivities. These results suggest that functional and structural abnormalities extend beyond the visual network in LHON patients. Such abnormalities also involve the auditory network, thus corroborating the notion of a cross-modal plasticity between these sensory modalities in patients with severe visual deficits.     

NPM1 Deletion Is Associated with Gross Chromosomal Rearrangements in Leukemia

Background

NPM1 gene at chromosome 5q35 is involved in recurrent translocations in leukemia and lymphoma. It also undergoes mutations in 60% of adult acute myeloid leukemia (AML) cases with normal karyotype. The incidence and significance of NPM1 deletion in human leukemia have not been elucidated.

Methodology and Principal Findings

Bone marrow samples from 145 patients with myelodysplastic syndromes (MDS) and AML were included in this study. Cytogenetically 43 cases had isolated 5q-, 84 cases had 5q- plus other changes and 18 cases had complex karyotype without 5q deletion. FISH and direct sequencing investigated the NPM1 gene. NPM1 deletion was an uncommon event in the “5q- syndrome” but occurred in over 40% of cases with high risk MDS/AML with complex karyotypes and 5q loss. It originated from large 5q chromosome deletions. Simultaneous exon 12 mutations were never found. NPM1 gene status was related to the pattern of complex cytogenetic aberrations. NPM1 haploinsufficiency was significantly associated with monosomies (p<0.001) and gross chromosomal rearrangements, i.e., markers, rings, and double minutes (p<0.001), while NPM1 disomy was associated with structural changes (p = 0.013). Interestingly, in complex karyotypes with 5q- TP53 deletion and/or mutations are not specifically associated with NPM1 deletion.

Conclusions and Significance

NPM1/5q35 deletion is a consistent event in MDS/AML with a 5q-/-5 in complex karyotypes. NPM1 deletion and NPM1 exon 12 mutations appear to be mutually exclusive and are associated with two distinct cytogenetic subsets of MDS and AML.     

Motor Learning in Healthy Humans Is Associated to Gray Matter Changes: A Tensor-Based Morphometry Study

We used tensor-based morphometry (TBM) to: 1) map gray matter (GM) volume changes associated with motor learning in young healthy individuals; 2) evaluate if GM changes persist three months after cessation of motor training; and 3) assess whether the use of different schemes of motor training during the learning phase could lead to volume modifications of specific GM structures. From 31 healthy subjects, motor functional assessment and brain 3D T1-weighted sequence were obtained: before motor training (time 0), at the end of training (two weeks) (time 2), and three months later (time 3). Fifteen subjects (group A) were trained with goal-directed motor sequences, and 16 (group B) with non purposeful motor actions of the right hand. At time 1 vs. time 0, the whole sample of subjects had GM volume increase in regions of the temporo-occipital lobes, inferior parietal lobule (IPL) and middle frontal gyrus, while at time 2 vs. time 1, an increased GM volume in the middle temporal gyrus was seen. At time 1 vs. time 0, compared to group B, group A had a GM volume increase of the hippocampi, while the opposite comparison showed greater GM volume increase in the IPL and insula in group B vs. group A. Motor learning results in structural GM changes of different brain areas which are part of specific neuronal networks and tend to persist after training is stopped. The scheme applied during the learning phase influences the pattern of such structural changes.     

Nucleophosmin is required for DNA integrity and p19Arf protein stability

Nucleophosmin (NPM) is a nucleolar phosphoprotein that binds the tumor suppressors p53 and p19(Arf) and is thought to be indispensable for ribogenesis, cell proliferation, and survival after DNA damage. The NPM gene is the most frequent target of genetic alterations in leukemias and lymphomas, though its role in tumorigenesis is unknown. We report here the first characterization of a mouse NPM knockout strain. Lack of NPM expression results in accumulation of DNA damage, activation of p53, widespread apoptosis, and mid-stage embryonic lethality. Fibroblasts explanted from null embryos fail to grow and rapidly acquire a senescent phenotype. Transfer of the NPM mutation into a p53-null background rescued apoptosis in vivo and fibroblast proliferation in vitro. Cells null for both p53 and NPM grow faster than control cells and are more susceptible to transformation by activated oncogenes, such as mutated Ras or overexpressed Myc. In the absence of NPM, Arf protein is excluded from nucleoli and is markedly less stable. Our data demonstrate that NPM regulates DNA integrity and, through Arf, inhibits cell proliferation and are consistent with a putative tumor-suppressive function of NPM.     

Crystallization of calcium carbonate salts into beta-chitin scaffold

Composites of beta-chitin with calcium carbonate polymorphs were prepared by precipitation of the mineral into a chitin scaffold by means of a double diffusion system. The beta-chitin was obtained from the pen of the Loligo sp. squid. The three main polymorphs of calcium carbonate: aragonite, calcite and vaterite, were observed. Their location within the matrix is a function of the polymorph. The supersaturation inside the compartmentalized space in the chitin governs the location and polymorphism of the crystals.     

Distribution of T cells bearing different forms of the T cell receptor gamma/delta in normal and pathological human tissues

Frozen sections from normal and pathologic human tissues were immunostained by the APAAP technique with three mAb directed against different epitopes of the TCR gamma delta; TCR delta 1 which binds to all cells bearing the TCR gamma delta; BB3 and delta TCS1 which, by immunoprecipitation studies, appear to react respectively with the disulfide-linked and nondisulfide-linked form of the TCR gamma delta. In normal thymus, TCR delta 1+ cells accounted for approximately 2% of the CD3+ thymocytes and were about three times more numerous in the medulla than in the cortex. TCR delta 1+ cells were mostly constituted by the delta TCS1 reactive subset (average ratio delta TCS1/BB3: 3.7). In the tonsil, the TCR delta 1+ cells (about 3% of CD3+ elements) were mainly located in the interfollicular area, where they frequently tended to arrange around high endothelium venules. In most samples, TCR delta 1+ cells were distributed beneath to the tonsil epithelium. Unlike thymus, the majority of TCR delta 1+ cells were usually constituted by the BB3-reactive subset (average BB3/delta TCS1 ratio: 2.0). A similar predominance of BB3+ over delta TCS1+ cells was also observed in normal peripheral blood. The spleen was the organ with the highest concentration of TCR delta 1+ cells that, like in the thymus, were mostly represented by delta TCS1+ elements. Noteworthy, the TCR delta 1+ cells were preferentially located in the splenic sinusoids while TCR alpha beta-bearing lymphocytes mostly occupied the periarteriolar sheaths of penicilliary arteries. The majority of neoplastic T cell proliferations studied lacked to express the TCR gamma delta. Two cases of beta F1-(TCR alpha beta-) T lymphoblastic lymphoma, however, were TCR gamma delta+ (delta TCS1+/BB3-). Both of them showed a stage II cortical phenotype, e.g., CD1+/CD3+/CD4+/CD8+/TCR delta 1+. Among inflammatory conditions, an increase of BB3+ cells was observed in close association with necrotic areas in cases of Kikuchi's and tuberculous lymphadenitis. The significance of this finding is under study.     

Inferred calcification rate of a temperate azooxanthellate caryophylliid coral along a wide latitudinal gradient

Correlations between environmental parameters (depth temperature and solar radiation) and growth parameters (bulk skeletal density, linear extension rate and net calcification rate) of the solitary azooxanthellate coral, Caryophyllia inornata, were investigated along an 8° latitudinal gradient on the western Italian coasts. Net calcification rate correlated positively with both bulk skeletal density and linear extension rate, showing that C. inornata allocates calcification resources evenly to thickening the skeleton and increasing linear growth. Overall, the three growth parameters did not follow gradients in the two environmental parameters, showing a different trend compared to most studies on zooxanthellate corals. However, the results are in agreement with the only previous analysis of an azooxanthellate coral, Leptopsammia pruvoti, studied along the same latitudinal gradient. In a comparison of the response to temperature of all Mediterranean species whose growth has been investigated to date, azooxanthellate corals were more tolerant to temperature increases than zooxanthellate corals.