Cholinergic Surveillance over Hippocampal RNA Metabolism and Alzheimer's-Like Pathology

The relationship between long-term cholinergic dysfunction and risk of developing dementia is poorly understood. Here we used mice with deletion of the vesicular acetylcholine transporter (VAChT) in the forebrain to model cholinergic abnormalities observed in dementia. Whole-genome RNA sequencing of hippocampal samples revealed that cholinergic failure causes changes in RNA metabolism. Remarkably, key transcripts related to Alzheimer's disease are affected. BACE1, for instance, shows abnormal splicing caused by decreased expression of the splicing regulator hnRNPA2/B1. Resulting BACE1 overexpression leads to increased APP processing and accumulation of soluble Aβ1-42. This is accompanied by age-related increases in GSK3 activation, tau hyperphosphorylation, caspase-3 activation, decreased synaptic markers, increased neuronal death, and deteriorating cognition. Pharmacological inhibition of GSK3 hyperactivation reversed deficits in synaptic markers and tau hyperphosphorylation induced by cholinergic dysfunction, indicating a key role for GSK3 in some of these pathological changes. Interestingly, in human brains there was a high correlation between decreased levels of VAChT and hnRNPA2/B1 levels with increased tau hyperphosphorylation. These results suggest that changes in RNA processing caused by cholinergic loss can facilitate Alzheimer's-like pathology in mice, providing a mechanism by which decreased cholinergic tone may increase risk of dementia

Repair of Parastomal Hernias with Biologic Grafts: A Systematic Review

Contains fulltext : 98303.pdf (publisher's version ) (Open Access)BACKGROUND: Biologic grafts are increasingly used instead of synthetic mesh for parastomal hernia repair due to concerns of synthetic mesh-related complications. This systematic review was designed to evaluate the use of these collagen-based scaffolds for the repair of parastomal hernias. METHODS: Studies were retrieved after searching the electronic databases MEDLINE, EMBASE and Cochrane CENTRAL. The search terms 'paracolostomy', 'paraileostomy', 'parastomal', 'colostomy', 'ileostomy', 'hernia', 'defect', 'closure', 'repair' and 'reconstruction' were used. Selection of studies and assessment of methodological quality were performed with a modified MINORS index. All reports on repair of parastomal hernias using a collagen-based biologic scaffold to reinforce or bridge the defect were included. Outcomes were recurrence rate, mortality and morbidity. RESULTS: Four retrospective studies with a combined enrolment of 57 patients were included. Recurrence occurred in 15.7% (95% confidence interval [CI] 7.8-25.9) of patients and wound-related complications in 26.2% (95% CI 14.7-39.5). No mortality or graft infections were reported. CONCLUSIONS: The use of reinforcing or bridging biologic grafts during parastomal hernia repair results in acceptable rates of recurrence and complications. However, given the similar rates of recurrence and complications achieved using synthetic mesh in this scenario, the evidence does not support use of biologic grafts

The impact of laxative use upon symptoms in patients with proven slow transit constipation

<p>Abstract</p> <p>Background</p> <p>Constipation severity is often defined by symptoms including feelings of complete evacuation, straining, stool frequency and consistency. These descriptors are mostly obtained in the absence of laxative use. For many constipated patients laxative usage is ubiquitous and long standing. Our aim was to determine the impact of laxative use upon the stereotypic constipation descriptors.</p> <p>Methods</p> <p>Patients with confirmed slow transit constipation completed 3-week stool diaries, detailing stool frequency and form, straining, laxative use and pain and bloating scores. Each diary day was classified as being under laxative affect (laxative affected days) or not (laxative unaffected days). Unconditional logistic regression was used to assess the affects of laxatives on constipation symptoms.</p> <p>Results</p> <p>Ninety four patients with scintigraphically confirmed slow transit constipation were enrolled in the study. These patients reported a stool frequency of 5.6 ± 4.3 bowel motions/week, only 21 patients reported <3 bowel motions/week. Similarly, 21 patients reported a predominant hard stool at defecation. The majority (90%) of patients reported regular straining. A regular feeling of complete evacuation was reported in just 7 patients. Daily pain and/or bloating were reported by 92% of patients. When compared with laxative unaffected days, on the laxative affected days patients had a higher stool frequency (OR 2.23; <it>P </it><0.001) and were more likely to report loose stools (OR 1.64; <it>P </it><0.009). Laxatives did not increase the number of bowel actions associated with a feeling of complete evacuation. Laxative use had no affect upon straining, pain or bloating scores</p> <p>Conclusions</p> <p>The reporting of frequent and loose stools with abdominal pain and/or bloating is common in patients with slow transit constipation. While laxative use is a significant contributor to altering stool frequency and form, laxatives have no apparent affect on pain or bloating or upon a patients feeling of complete evacuation. These factors need to be taken into account when using constipation symptoms to define this population.</p

Multipurpose silicon photonics signal processor core

[EN] Integrated photonics changes the scaling laws of information and communication systems offering architectural choices that combine photonics with electronics to optimize performance, power, footprint, and cost. Application-specific photonic integrated circuits, where particular circuits/chips are designed to optimally perform particular functionalities, require a considerable number of design and fabrication iterations leading to long development times. A different approach inspired by electronic Field Programmable Gate Arrays is the programmable photonic processor, where a common hardware implemented by a two-dimensional photonic waveguide mesh realizes different functionalities through programming. Here, we report the demonstration of such reconfigurable waveguide mesh in silicon. 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Mre11-Rad50 Promotes Rapid Repair of DNA Damage in the Polyploid Archaeon Haloferax volcanii by Restraining Homologous Recombination

Polyploidy is frequent in nature and is a hallmark of cancer cells, but little is known about the strategy of DNA repair in polyploid organisms. We have studied DNA repair in the polyploid archaeon Haloferax volcanii, which contains up to 20 genome copies. We have focused on the role of Mre11 and Rad50 proteins, which are found in all domains of life and which form a complex that binds to and coordinates the repair of DNA double-strand breaks (DSBs). Surprisingly, mre11 rad50 mutants are more resistant to DNA damage than the wild-type. However, wild-type cells recover faster from DNA damage, and pulsed-field gel electrophoresis shows that DNA double-strand breaks are repaired more slowly in mre11 rad50 mutants. Using a plasmid repair assay, we show that wild-type and mre11 rad50 cells use different strategies of DSB repair. In the wild-type, Mre11-Rad50 appears to prevent the repair of DSBs by homologous recombination (HR), allowing microhomology-mediated end-joining to act as the primary repair pathway. However, genetic analysis of recombination-defective radA mutants suggests that DNA repair in wild-type cells ultimately requires HR, therefore Mre11-Rad50 merely delays this mode of repair. In polyploid organisms, DSB repair by HR is potentially hazardous, since each DNA end will have multiple partners. We show that in the polyploid archaeon H. volcanii the repair of DSBs by HR is restrained by Mre11-Rad50. The unrestrained use of HR in mre11 rad50 mutants enhances cell survival but leads to slow recovery from DNA damage, presumably due to difficulties in the resolution of DNA repair intermediates. Our results suggest that recombination might be similarly repressed in other polyploid organisms and at repetitive sequences in haploid and diploid species

Matrix Recruitment and Calcium Sequestration for Spatial Specific Otoconia Development

Otoconia are bio-crystals anchored to the macular sensory epithelium of the utricle and saccule in the inner ear for motion sensing and bodily balance. Otoconia dislocation, degeneration and ectopic calcification can have detrimental effects on balance and vertigo/dizziness, yet the mechanism underlying otoconia formation is not fully understood. In this study, we show that selected matrix components are recruited to form the crystal matrix and sequester Ca2+ for spatial specific formation of otoconia. Specifically, otoconin-90 (Oc90) binds otolin through both domains (TH and C1q) of otolin, but full-length otolin shows the strongest interaction. These proteins have much higher expression levels in the utricle and saccule than other inner ear epithelial tissues in mice. In vivo, the presence of Oc90 in wildtype (wt) mice leads to an enrichment of Ca2+ in the luminal matrices of the utricle and saccule, whereas absence of Oc90 in the null mice leads to drastically reduced matrix-Ca2+. In vitro, either Oc90 or otolin can increase the propensity of extracellular matrix to calcify in cell culture, and co-expression has a synergistic effect on calcification. Molecular modeling and sequence analysis predict structural features that may underlie the interaction and Ca2+-sequestering ability of these proteins. Together, the data provide a mechanism for the otoconial matrix assembly and the role of this matrix in accumulating micro-environmental Ca2+ for efficient CaCO3 crystallization, thus uncover a critical process governing spatial specific otoconia formation

Business Ethics: The Promise of Neuroscience

Recent advances in cognitive neuroscience research portend well for furthering understanding of many of the fundamental questions in the field of business ethics, both normative and empirical. This article provides an overview of neuroscience methodology and brain structures, and explores the areas in which neuroscience research has contributed findings of value to business ethics, as well as suggesting areas for future research. Neuroscience research is especially capable of providing insight into individual reactions to ethical issues, while also raising challenging normative questions about the nature of moral responsibility, autonomy, intent, and free will. This article also provides a brief summary of the papers included in this special issue, attesting to the richness of scholarly inquiry linking neuroscience and business ethics. We conclude that neuroscience offers considerable promise to the field of business ethics, but we caution against overpromise