NINJ2 SNP may affect the onset age of first-ever ischemic stroke without increasing silent cerebrovascular lesions

<p>Abstract</p> <p>Background</p> <p>To investigate if single nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene <it>NINJ2 </it>would be associated with earlier-onset (vs. late-onset) first-ever ischemic stroke and increase silent cerebrovascular lesions prior to the manifestation of the stroke.</p> <p>Methods</p> <p>We prospectively enrolled 164 patients (67.6 ± 12.9 years, 92 men) admitted with first-ever ischemic strokes. All patients underwent genotyping of rs11833579 and rs12425791 as well as systemic investigations including magnetic resonance (MR) imaging and other vascular workup. Stroke-related MR lesions were registered on a brain-template-set using a custom-built software package 'Image_QNA': high-signal-intensity ischemic lesions on diffusion, T2-weighted, or fluid attenuation inversion recovery (FLAIR) MR images, and low signal intensity hemorrhagic lesions on gradient-echo MR images.</p> <p>Results</p> <p>The rs11833579 A/A or G/A genotype was independently associated with the first-ever ischemic stroke before the age 59 vs. 59 or over, after adjusting for cardiovascular risk factors and prior medication of antiplatelet or anticoagulant drugs, increasing the risk by about 2.5 fold. In the quantitative MR lesion maps from age-sex matched subgroups (n = 124 or 126), there was no difference between the patients with the rs11833579 A/A or G/A genotype and those with the G/G genotype. Unexpectedly, the extent of leukoaraiosis on FLAIR-MR images tended to be smaller in the corona radiata and centrum semiovale of the patients with the rs12425791 A/A or G/A genotype than in those with the G/G genotype (<it>P </it>= 0.052). Neither the rs11833579 nor the rs12425791 genotype significantly affected initial stroke severity; however the latter was associated with relatively low modified Rankin scale scores at 1 year after stroke.</p> <p>Conclusions</p> <p>The rs11833579 A/A or G/A genotype may bring forward the onset age of first-ever ischemic stroke without increasing silent cerebrovascular lesions prior to the stroke. Further studies are required to confirm our preliminary findings.</p

Spatial Extent of Charge Repulsion Regulates Assembly Pathways for Lysozyme Amyloid Fibrils

Formation of large protein fibrils with a characteristic cross β-sheet architecture is the key indicator for a wide variety of systemic and neurodegenerative amyloid diseases. Recent experiments have strongly implicated oligomeric intermediates, transiently formed during fibril assembly, as critical contributors to cellular toxicity in amyloid diseases. At the same time, amyloid fibril assembly can proceed along different assembly pathways that might or might not involve such oligomeric intermediates. Elucidating the mechanisms that determine whether fibril formation proceeds along non-oligomeric or oligomeric pathways, therefore, is important not just for understanding amyloid fibril assembly at the molecular level but also for developing new targets for intervening with fibril formation. We have investigated fibril formation by hen egg white lysozyme, an enzyme for which human variants underlie non-neuropathic amyloidosis. Using a combination of static and dynamic light scattering, atomic force microscopy and circular dichroism, we find that amyloidogenic lysozyme monomers switch between three different assembly pathways: from monomeric to oligomeric fibril assembly and, eventually, disordered precipitation as the ionic strength of the solution increases. Fibril assembly only occurred under conditions of net repulsion among the amyloidogenic monomers while net attraction caused precipitation. The transition from monomeric to oligomeric fibril assembly, in turn, occurred as salt-mediated charge screening reduced repulsion among individual charged residues on the same monomer. We suggest a model of amyloid fibril formation in which repulsive charge interactions are a prerequisite for ordered fibril assembly. Furthermore, the spatial extent of non-specific charge screening selects between monomeric and oligomeric assembly pathways by affecting which subset of denatured states can form suitable intermolecular bonds and by altering the energetic and entropic requirements for the initial intermediates emerging along the monomeric vs. oligomeric assembly path

Role of Synucleins in Alzheimer’s Disease

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common causes of dementia and movement disorders in the elderly. While progressive accumulation of oligomeric amyloid-β protein (Aβ) has been identified as one of the central toxic events in AD leading to synaptic dysfunction, accumulation of α-synuclein (α-syn) resulting in the formation of oligomers has been linked to PD. Most of the studies in AD have been focused on investigating the role of Aβ and Tau; however, recent studies suggest that α-syn might also play a role in the pathogenesis of AD. For example, fragments of α-syn can associate with amyloid plaques and Aβ promotes the aggregation of α-syn in vivo and worsens the deficits in α-syn tg mice. Moreover, α-syn has also been shown to accumulate in limbic regions in AD, Down’s syndrome, and familial AD cases. Aβ and α-syn might directly interact under pathological conditions leading to the formation of toxic oligomers and nanopores that increase intracellular calcium. The interactions between Aβ and α-syn might also result in oxidative stress, lysosomal leakage, and mitochondrial dysfunction. Thus, better understanding the steps involved in the process of Aβ and α-syn aggregation is important in order to develop intervention strategies that might prevent or reverse the accumulation of toxic proteins in AD

Investigating the Nature of the Luminous Ambiguous Nuclear Transient ASASSN-17jz

We present observations of the extremely luminous but ambiguous nuclear transient (ANT) ASASSN-17jz, spanning roughly 1200 days of the object's evolution. ASASSN-17jz was discovered by the All-Sky Automated Survey for Supernovae (ASAS-SN) in the galaxy SDSS J171955.84+414049.4 on UT 2017 July 27 at a redshift of z = 0.1641. The transient peaked at an absolute B-band magnitude of M B,peak = -22.81, corresponding to a bolometric luminosity of L bol,peak = 8.3 × 1044 erg s-1, and exhibited late-time ultraviolet emission that was still ongoing in our latest observations. Integrating the full light curve gives a total emitted energy of E tot = (1.36 ±0.08) × 1052 erg, with (0.80 ± 0.02) × 1052 erg of this emitted within 200 days of peak light. This late-time ultraviolet emission is accompanied by increasing X-ray emission that becomes softer as it brightens. ASASSN-17jz exhibited a large number of spectral emission lines most commonly seen in active galactic nuclei (AGNs) with little evidence of evolution. It also showed transient Balmer features, which became fainter and broader over time, and are still being detected >1000 days after peak brightness. We consider various physical scenarios for the origin of the transient, including supernovae (SNe), tidal disruption events, AGN outbursts, and ANTs. We find that the most likely explanation is that ASASSN-17jz was a SN IIn occurring in or near the disk of an existing AGN, and that the late-time emission is caused by the AGN transitioning to a more active state

Past, Present, and Future X-Ray and Gamma-Ray Missions

X- and -ray astronomy began in the early sixties of the last century with balloons flights, sounding rocket experiment and satellites. Long before space satellite detected X- and -rays emitted by cosmic sources, scientists had known that the Universe should be producing these photons. In this chapter we provided an overview of past and present missions that has made the X- and -ray astronomy an integral part of astronomical research, and prospects of future developments

‘In sight, out of mind’: The experiences of the compliantly engaged community psychiatric out-patient

Research on engagement within communitybased psychiatric services in the UK has mainly focussed on factors related to those 'at risk' of non-attendance or non-compliance, with the tacit assumption that those in regular attendance are largely content and hence not a priority. The present study systematically explored the experiences and views of 25 people with severe and enduring mental illness who had regularly attended out-patient settings for more than 5 years. Regular attendance at consultations was not synonymous with satisfaction - in fact it masked varying levels of unmet needs and 'de-humanisation'. In order to establish and maintain non-coercive community services that prioritise 'recovery' above illness and 'risk' containment, it is essential that the experiences of people in established and apparently 'less troublesome' therapeutic relationships are also taken into account and integrated into policy and practice. © Springer Science+Business Media, LLC 2011