Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases.

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts

Quantum critical states and phase transitions in the presence of non equilibrium noise

Quantum critical points are characterized by scale invariant correlations and correspondingly long ranged entanglement. As such, they present fascinating examples of quantum states of matter, the study of which has been an important theme in modern physics. Nevertheless very little is known about the fate of quantum criticality under non equilibrium conditions. In this paper we investigate the effect of external noise sources on quantum critical points. It is natural to expect that noise will have a similar effect to finite temperature, destroying the subtle correlations underlying the quantum critical behavior. Surprisingly we find that in many interesting situations the ubiquitous 1/f noise preserves the critical correlations. The emergent states show intriguing interplay of intrinsic quantum critical and external noise driven fluctuations. We demonstrate this general phenomenon with specific examples in solid state and ultracold atomic systems. Moreover our approach shows that genuine quantum phase transitions can exist even under non equilibrium conditions.Comment: 9 pages, 2 figure

Sexual Size Dimorphism and Body Condition in the Australasian Gannet

Funding: The research was financially supported by the Holsworth Wildlife Research Endowment. Acknowledgments We thank the Victorian Marine Science Consortium, Sea All Dolphin Swim, Parks Victoria, and the Point Danger Management Committee for logistical support. We are grateful for the assistance of the many field volunteers involved in the study.Peer reviewedPublisher PD

Zinc-Regulated DNA Binding of the Yeast Zap1 Zinc-Responsive Activator

The Zap1 transcription factor of Saccharomyces cerevisiae plays a central role in zinc homeostasis by controlling the expression of genes involved in zinc metabolism. Zap1 is active in zinc-limited cells and repressed in replete cells. At the transcriptional level, Zap1 controls its own expression via positive autoregulation. In addition, Zap1's two activation domains are regulated independently of each other by zinc binding directly to those regions and repressing activation function. In this report, we show that Zap1 DNA binding is also inhibited by zinc. DMS footprinting showed that Zap1 target gene promoter occupancy is regulated with or without transcriptional autoregulation. These results were confirmed using chromatin immunoprecipitation. Zinc regulation of DNA binding activity mapped to the DNA binding domain indicating other parts of Zap1 are unnecessary for this control. Overexpression of Zap1 overrode DNA binding regulation and resulted in constitutive promoter occupancy. Under these conditions of constitutive binding, both the zinc dose response of Zap1 activity and cellular zinc accumulation were altered suggesting the importance of DNA binding control to zinc homeostasis. Thus, our results indicated that zinc regulates Zap1 activity post-translationally via three independent mechanisms, all of which contribute to the overall zinc responsiveness of Zap1

A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan

BACKGROUND: Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized clinically by resting tremor, bradykinesia, postural instability and rigidity. The prevalence of PD is approximately 2% of the population over 65 years of age and 1.7 million PD patients (age ≥ 55 years) live in China. Recently, a common LRRK2 variant Gly2385Arg was reported in ethnic Chinese PD population in Taiwan. We analyzed the frequency of this variant in our independent PD case-control population of Han Chinese from Taiwan. METHODS: 305 patients and 176 genetically unrelated healthy controls were examined by neurologists and the diagnosis of PD was based on the published criteria. The region of interest was amplified with standard polymerase chain reaction (PCR). PCR fragments then were directly sequenced in both forward and reverse directions. Differences in genotype frequencies between groups were assessed by the X(2 )test, while X(2 )analysis was used to test for the Hardy-Weinberg equilibrium. RESULTS: Of the 305 patients screened we identified 27 (9%) with heterozygous G2385R variant. This mutation was only found in 1 (0.5%) in our healthy control samples (odds ratio = 16.99, 95% CI: 2.29 to 126.21, p = 0.0002). Sequencing of the entire open reading frame of LRRK2 in G2385R carriers revealed no other variants. CONCLUSION: These data suggest that the G2385R variant contributes significantly to the etiology of PD in ethnic Han Chinese individuals. With consideration of the enormous and expanding aging Chinese population in mainland China and in Taiwan, this variant is probably the most common known genetic factor for PD worldwide

PDMS microfluidics developed for polymer based photonic biosensors

In this work, advances in the fabrication technology and functional analysis of a polymer microfluidic system-as a significant part of a developed polymer photonic biosensor-are reported. Robust and cost-effective microfluidics in PDMS including sample preparation functions is designed and realized by using SU-8 moulding replica. Surface modification strategies using Triton X-100 and PDMS-PEO and their effect on device sealing and non-specific protein adsorption are investigated by contact angle measurement and in situ fluorescence microscopy. © 2014 Springer-Verlag Berlin Heidelberg

Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution

It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons (“exon-intron marking”), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing

Multi-ancestry genome-wide association meta-analysis of Parkinson's disease.

Although over 90 independent risk variants have been identified for Parkinson's disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson's disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Impact of the "Tobacco control law" on exposure to environmental tobacco smoke in Spain

<p>Abstract</p> <p>Background</p> <p>The initial evaluations of the introduction of legislation that regulates smoking in enclosed public places in European countries, describe an important effect in the control of exposure to environmental tobacco smoke. However, the evidence is still limited. The objective of this study is to estimate the short-term effects of the comprehensive "Tobacco control law" introduced in Spain on January 2006, which includes a total ban of smoking in workplaces and a partial limitation of smoking in bars and restaurants.</p> <p>Methods</p> <p>Cross-sectional, population-based study. The self-reported exposure to environmental tobacco smoke at home, at work, in bars and restaurants of the population aged 18 to 64 years in the Madrid Region during a period prior to the law (October and November 2005; n = 1750) was compared to that of the period immediately after the law came into force (January-July 2006; n = 1252). Adjusted odds ratios (OR) were calculated using logistic regression models.</p> <p>Results</p> <p>Passive exposure to tobacco smoke at home has hardly changed. However, at indoor workplaces there has been a considerable reduction: after the law came into force the OR for daily exposure > 0–3 hours versus non-exposure was 0.11 (95% CI: 0.07 to 0.17) and for more than 3 hours, 0.12 (95% CI: 0.09 to 0.18). For fairly high exposure in bars and restaurants versus non-exposure, the OR in the former was 0.30 (95% CI: 0.20 to 0.44) and in the latter was 0.24 (95% CI: 0.18 to 0.32); for very high exposure versus non-exposure they were 0.16 (95% CI: 0.10 to 0.24) and 0.11 (95% CI: 0.07 to 0.19), respectively. These results were similar for the smoking and non-smoking populations.</p> <p>Conclusion</p> <p>A considerable reduction in exposure to environmental tobacco smoke in the workplace and, to a lesser extent, in bars and restaurants, is related to the implementation of the "Tobacco control law". Although only initial figures, these results already demonstrate the effectiveness of strategies that establish control measures to guarantee smoke-free places.</p

Diffuse idiopathic skeletal hyperostosis (DISH): relation to vertebral fractures and bone density

UnlabelledRadiographs and spinal bone mineral density (BMD) were evaluated from 342 elderly men regarding possible effects of diffuse idiopathic skeletal hyperostosis (DISH) on vertebral fractures and densitometry measurements. Prevalent vertebral fractures were more frequent among men with DISH compared to men with no DISH even after fracture prevalence was adjusted for BMD. Paravertebral calcifications should be considered in patients with DISH when interpreting BMD measurements because both dual X-ray absorptiometry (DXA) and quantitative CT (QCT) densitometry may not be reliable.IntroductionThe purpose of this study is to evaluate the prevalence of DISH in older men and its association with vertebral fractures and with BMD determined by DXA and QCT.MethodsLateral radiographs of the spine were analyzed in a sample of 342 men aged ≥ 65 years participating in the MrOS Study concerning the presence and grade of DISH and vertebral fractures. Lumbar BMD was measured by both DXA (areal, grams per square centimeter) and QCT (volumetric, grams per cubic centimeter). The association between DISH, BMD, and presence of fractures was studied using χ ( 2 ) and t tests.ResultsDISH was present in 52% (178/342) of the men. Men with DISH were older (mean, 75.1 vs 73.3, p &lt; 0.05) and more likely to have prevalent fractures (28% vs 20%, p &lt; p = 0.09). BMD assessed with DXA (1.08 vs 1.00 g/cm(2), p ≤ 0.0001), but not with QCT (0.11 vs 0.11 g/cm3, p = 0.65), was significantly higher in men with DISH compared to men without DISH. Significantly lower BMD of men with both DISH and fractures compared to men with DISH but without fractures was only detected by QCT (-25%, 0.09 vs 0.12, p &lt; 0.05). Both DXA BMD and QCT BMD were significantly higher in severe lumbar DISH (+22% and +31%, p &lt; 0.0001), respectively.ConclusionDISH was associated with a higher prevalence of vertebral fractures in elderly men. Lumbar ossifications related to DISH should be considered when interpreting BMD measurements to predict their fracture risk