Cortical Grey Matter and Subcortical White Matter Brain Microstructural Changes in Schizophrenia Are Localised and Age Independent: A Case-Control Diffusion Tensor Imaging Study

It is still unknown whether the structural brain impairments that characterize schizophrenia (SZ) worsen during the lifetime. Here, we aimed to describe age-related microstructural brain changes in cortical grey matter and subcortical white matter of patients affected by SZ. In this diffusion tensor imaging study, we included 69 patients diagnosed with SZ and 69 healthy control (HC) subjects, age and gender matched. We carried out analyses of covariance, with diagnosis as fixed factor and brain diffusion-related parameters as dependent variables, and controlled for the effect of education. White matter fractional anisotropy decreased in the entire age range spanned (18–65 years) in both SZ and HC and was significantly lower in younger patients with SZ, with no interaction (age by diagnosis) effect in fiber tracts including corpus callosum, corona radiata, thalamic radiations and external capsule. Also, grey matter mean diffusivity increased in the entire age range in both SZ and HC and was significantly higher in younger patients, with no age by diagnosis interaction in the left frontal operculum cortex, left insula and left planum polare and in the right temporal pole and right intracalcarine cortex. In individuals with SZ we found that localized brain cortical and white matter subcortical microstructural impairments appear early in life but do not worsen in the 18–65 year age range.     

Ubiquitin Regulates GGA3-mediated Degradation of BACE1

BACE1 (β-site amyloid precursor protein-cleaving enzyme 1) is a membrane-tethered member of the aspartyl proteases, essential for the production of β-amyloid, a toxic peptide that accumulates in the brain of subjects affected by Alzheimer disease. The BACE1 C-terminal fragment contains a DXXLL motif that has been shown to bind the VHS (VPS27, Hrs, and STAM) domain of GGA1–3 (Golgi-localized γ-ear-containing ARF-binding proteins). GGAs are trafficking molecules involved in the transport of proteins containing the DXXLL signal from the Golgi complex to endosomes. Moreover, GGAs bind ubiquitin and traffic synthetic and endosomal ubiquitinated cargoes to lysosomes. We have previously shown that depletion of GGA3 results in increased BACE1 levels and activity because of impaired lysosomal degradation. Here, we report that the accumulation of BACE1 is rescued by the ectopic expression of GGA3 in H4 neuroglioma cells depleted of GGA3. Accordingly, the overexpression of GGA3 reduces the levels of BACE1 and β-amyloid. We then established that mutations in the GGA3 VPS27, Hrs, and STAM domain (N91A) or in BACE1 di-leucine motif (L499A/L500A), able to abrogate their binding, did not affect the ability of ectopically expressed GGA3 to rescue BACE1 accumulation in cells depleted of GGA3. Instead, we found that BACE1 is ubiquitinated at lysine 501 and is mainly monoubiquitinated and Lys-63-linked polyubiquitinated. Finally, a GGA3 mutant with reduced ability to bind ubiquitin (GGA3L276A) was unable to regulate BACE1 levels both in rescue and overexpression experiments. These findings indicate that levels of GGA3 tightly and inversely regulate BACE1 levels via interaction with ubiquitin sorting machinery.     

Material and surface factors influencing backside fretting wear in total knee replacement tibial components

Retrieval studies have shown that the interface between the ultra-high molecular weight polyethylene insert and metal tibial tray of fixed-bearing total knee replacement components can be a source of substantial amounts of wear debris due to fretting micromotion. We assessed fretting wear of polyethylene against metal as a function of metal surface finish, alloy, and micromotion amplitude, using a three-station pin-on-disc fretting wear simulator. Overall, the greatest reduction in polyethylene wear was achieved by highly polishing the metal surface. For example, highly polished titanium alloy surfaces produced nearly 20 times less polyethylene wear compared with blasted titanium alloy, whereas, decreasing the micromotion amplitude from 200 to 50 μm produced approximately four times less polyethylene wear for the same blasted titanium alloy surface. Although the effect of the metal alloy was much smaller than the effect of metal surface roughness or the micromotion amplitude, CoCr discs produced slightly greater polyethylene fretting wear than titanium alloy discs under each condition. The results are essential in design and manufacturing decisions related to fixed-bearing total knee replacements.     

Exome sequencing reveals VCP mutations as a cause of familial ALS

Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in?families with Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ～1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.     

Guanosine 5′‐diphosphate 3′‐diphosphate (ppGpp) as a negative modulator of polynucleotide phosphorylase activity in a ‘rare’ actinomycete

With the beginning of the idiophase the highly phosphorylated guanylic nucleotides guanosine 5′‐diphosphate 3′‐diphosphate (ppGpp) and guanosine 5′‐triphosphate 3′‐diphosphate (pppGpp), collectively referred to as (p)ppGpp, activate stress survival adaptation programmes and trigger secondary metabolism in actinomycetes. The major target of (p)ppGpp is the RNA polymerase, where it binds altering the enzyme activity. In this study analysis of the polynucleotide phosphorylase (PNPase)‐encoding gene pnp mRNA, in Nonomuraea sp. ATCC 39727 wild‐type, constitutively stringent and relaxed strains, led us to hypothesize that in actinomycetes (p)ppGpp may modulate gene expression at the level of RNA decay also. This hypothesis was supported by: (i) in vitro evidence that ppGpp, at physiological levels, inhibited both polynucleotide polymerase and phosphorolytic activities of PNPase in Nonomuraea sp., but not in Escherichia coli, (ii) in vivo data showing that the pnp mRNA and the A40926 antibiotic cluster‐specific dpgA mRNA were stabilized during the idiophase in the wild‐type strain but not in a relaxed mutant and (iii) measurement of chemical decay of pulse‐labelled bulk mRNA. The results of biochemical tests suggest competitive inhibition of ppGpp with respect to nucleoside diphosphates in polynucleotide polymerase assays and mixed inhibition with respect to inorganic phosphate when the RNA phosphorolytic activity was determined.     

Synthesis and pharmacological characterization of 5-phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-ones: a new class of Neuropeptide S antagonists

A new class of selective NPS antagonist was developed starting from a commercially available product identified by screening activities. Experimental NMR observations and computational experiments allowed the discovery of a new class of derivatives. 5-Phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one represents a new lead compound in the NPS antagonist field.     

A new β-chain haemoglobin variant with increased oxygen affinity: Hb Roma [β115(g17)Ala → Val]

Background

Haemoglobin Roma [β115(G17)Ala → Val] is a new adult haemoglobin variant found in a patient presenting a mild hypochromia and microcytosis. We studied this previously uncharacterised variant in order to evaluate the effect on the structural and funcional properties of the Ala → Val substitution at the α1β1 interface.

Methods and results

The variant chain was identified by direct DNA sequencing of the β-globin gene, which revealed a GCC → GTC mutation in codon 115. This mutation was confirmed by mass spectrometric analysis of the tetramers and peptides. The oxygen-binding properties of the haemoglobin A/haemoglobin Roma mixture, in which the variant makes up 25% of the haemoglobins, showed a significant increase in oxygen affinity with respect to normal haemoglobin A, both in the absence and presence of 2,3-bisphosphoglycerate. The role of the βG17 position, situated at the α₁β₁ interface, has been examined using computational models of haemoglobin Roma and other known βG17 variants, in comparison with normal haemoglobin A.

Conclusions

This study suggests that the β115(G17)Ala → Val substitution at the α1β1 interface is responsible for increased oxygen affinity and mild destabilisation of the haemoglobin Roma.

General significance

An amino acid substitution at the G17 position of the α1β1 interface may result in stabilisation of the high affinity R-state of the haemoglobin molecule.     

<Emphasis Type="Italic">Membraniporopsis tubigera</Emphasis>, an invasive bryozoan in sandy beaches of southern Brazil and Uruguay

The massive irruption of the invasive bryozoan Membraniporopsis tubigera (Osburn) in sandy beaches of southern Brazil and Uruguay is reported. The species, originally described from Puerto Rico, Texas and Florida, has also been recorded for Brazilian beaches from 21°S to 26°S as well as for harbours of Australia, New Zealand and the Sea of Japan. The southward spreading rate of this bryozoan along the Brazilian and Uruguayan coasts can be estimated in approximately 183–195 km year⁻¹. The chances that this invasion could proceed southwards in the Southwest Atlantic and the possible impacts that it may be causing are discussed. The case of M. tubigera seems to be qualitatively and quantitatively different from those of other alien bryozoans previously recorded for this region, since it appeared massively in exposed sandy beaches, a habitat regarded to date as apparently free from the pervasive ecological impact of invasion by exotic species in the Southwest Atlantic.     

Patterns of cortical activity during the observation of Public Service Announcements and commercial advertisings

Background

In the present research we were interested to study the cerebral activity of a group of healthy subjects during the observation a documentary intermingled by a series of TV advertisements. In particular, we desired to examine whether Public Service Announcements (PSAs) are able to elicit a different pattern of activity, when compared with a different class of commercials, and correlate it with the memorization of the showed stimuli, as resulted from a following subject’s verbal interview.

Methods

We recorded the EEG signals from a group of 15 healthy subjects and applied the High Resolution EEG techniques in order to estimate and map their Power Spectral Density (PSD) on a realistic cortical model. The single subjects’ activities have been z-score transformed and then grouped to define four different datasets, related to subjects who remembered and forgotten the PSAs and to subjects who remembered and forgotten cars commercials (CAR) respectively, which we contrasted to investigate cortical areas involved in this encoding process.

Results

The results we here present show that the cortical activity elicited during the observation of the TV commercials that were remembered (RMB) is higher and localized in the left frontal brain areas when compared to the activity elicited during the vision of the TV commercials that were forgotten (FRG) in theta and gamma bands for both categories of advertisements (PSAs and CAR). Moreover, the cortical maps associated with the PSAs also show an increase of activity in the alpha and beta band.

Conclusions

In conclusion, the TV advertisements that will be remembered by the experimental population have increased their cerebral activity, mainly in the left hemisphere. These results seem to be congruent with and well inserted in the already existing literature, on this topic, related to the HERA model. The different pattern of activity in different frequency bands elicited by the observation of PSAs may be justified by the existence of additional cortical networks processing these kind of audiovisual stimuli. Further research with an extended set of subjects will be necessary to further validate the observations reported in this paper.