Cell death pathology: Cross-talk with autophagy and its clinical implications

AbstractAutophagy is a self-digesting mechanism that cells adopt to respond to stressful stimuli. Morphologically, cells dying by autophagy show multiple cytoplasmic double-membraned vacuoles, and, if prolonged, autophagy can lead to cell death, "autophagic cell death". Thus, autophagy can act both as a temporary protective mechanism during a brief stressful episode and be a mode of cell death in its own right. In this mini-review we focus on recent knowledge concerning the connection between autophagy and programmed cell death, evaluating their possible implications for therapy in pathologies like cancer and neurodegeneration

The molecular epidemiology of variant CJD

The emergence of the novel prion diseases bovine spongiform encephalopathy (BSE) and, subsequently, variant Creutzfeldt-Jakob disease (vCJD) in epidemic forms has attracted much scientific attention. The oral transmission of these disorders, the causative relationship of vCJD to BSE and the resistance of the transmissible agents in both disorders to conventional forms of decontamination has caused great public health concern. The size of the still emerging vCJD epidemic is thankfully much lower than some early published estimates. This paper reviews current knowledge of the factors that influence the development of vCJD: the properties of the infectious agent; the route of inoculation and individual susceptibility factors. The current epidemiological data are reviewed, along with relevant animal transmission studies. In terms of genetic susceptibility, the best characterised is the common single nucleotide polymorphism at codon 129 of prion protein gene. Current biomarkers and future areas of research will be discussed. These issues are important in informing precautionary measures and the ongoing monitoring of vCJD

Analysis by x-ray microtomography of a granular packing undergoing compaction

Several acquisitions of X-ray microtomography have been performed on a beads packing while it compacts under vertical vibrations. An image analysis allows to study the evolution of the packing structure during its progressive densification. In particular, the volume distribution of the pores reveals a large tail, compatible to an exponential law, which slowly reduces as the system gets more compact. This is quite consistent, for large pores, with the free volume theory. These results are also in very good agreement with those obtained by a previous numerical model of granular compaction.Comment: 4 pages, 4 figures. Latex (revtex4). to be published in Phys. Rev.

Neural Correlates of Attentional and Mnemonic Processing in Event-Based Prospective Memory

Prospective memory (PM), or memory for realizing delayed intentions, was examined with an event-based paradigm while simultaneously measuring neural activity with high-density EEG recordings. Specifically, the neural substrates of monitoring for an event-based cue were examined, as well as those perhaps associated with the cognitive processes supporting detection of cues and fulfillment of intentions. Participants engaged in a baseline lexical decision task (LDT), followed by a LDT with an embedded PM component. Event-based cues were constituted by color and lexicality (red words). Behavioral data provided evidence that monitoring, or preparatory attentional processes, were used to detect cues. Analysis of the event-related potentials (ERP) revealed visual attentional modulations at 140 and 220 ms post-stimulus associated with preparatory attentional processes. In addition, ERP components at 220, 350, and 400 ms post-stimulus were enhanced for intention-related items. Our results suggest preparatory attention may operate by selectively modulating processing of features related to a previously formed event-based intention, as well as provide further evidence for the proposal that dissociable component processes support the fulfillment of delayed intentions

The incidence, prevalence and mortality of granulomatosis with polyangiitis in the UK Clinical Practice Research Datalink

Objectives: To estimate the incidence, prevalence and mortality of Granulomatosis with polyangiitis (GPA) in the United Kingdom. Methods: We conducted a historical cohort study using data from the Clinical Practice Research Datalink and Hospital Episode Statistics (CPRD-HES). We calculated incidence rate ratios, adjusted for age, gender and ethnicity, using Poisson regression. Results: We identified 462 cases diagnosed between 1997 and 2013. Our overall estimate of incidence was 11.8 (95% CI 10.7-12.9)/million person-years. Incidence in children (aged <16 years) was 0.88 (95% CI 0.40-1.96), and adults 14.0 (95% CI 12.8-15.4). The incidence was lower in females (adjusted IRR 0.68; 95% CI 0.56-0.81) and highest in the 55-69 year age-group (adjusted IRR 9.5, 95% CI 6.9-13.0; reference group 0-39 years). Incidence was not significantly different in the Black / Minority Ethnic population compared to the white population (adjusted odds ratio 0.78, 95% CI 0.53-1.13, p=0.13). The prevalence in 2013 was 134.9 (121.3-149.6) /million. Mortality was 13.6% at 1-year, and higher in HES than CPRD-identified cases (Hazard ratio 3.16, 95% CI 2.19-4.56, p<0.001). Conclusions: By combining primary and secondary care datasets we have found the incidence and mortality of granulomatosis with polyangiitis to be higher than previously reported. We predict that at present each year in the UK there will be approximately 700 new cases of whom 95 will die within 12 months

TAp73 promotes anabolism

Metabolic adaptation has emerged as a hallmark of cancer and a promising therapeutic target, as rapidly proliferating cancer cells adapt their metabolism increasing nutrient uptake and reorganizing metabolic fluxes to support biosynthesis. The transcription factor p73 belongs to the p53-family and regulates tumorigenesis via its two N-terminal isoforms, with (TAp73) or without (ΔNp73) a transactivation domain. TAp73 acts as tumor suppressor, at least partially through induction of cell cycle arrest and apoptosis and through regulation of genomic stability. Here, we sought to investigate whether TAp73 also affects metabolic profiling of cancer cells. Using high throughput metabolomics, we unveil a thorough and unexpected role for TAp73 in promoting Warburg effect and cellular metabolism. TAp73-expressing cells show increased rate of glycolysis, higher amino acid uptake and increased levels and biosynthesis of acetyl-CoA. Moreover, we report an extensive TAp73-mediated upregulation of several anabolic pathways including polyamine and synthesis of membrane phospholipids. TAp73 expression also increases cellular methyl-donor S-adenosylmethionine (SAM), possibly influencing methylation and epigenetics, and promotes arginine metabolism, suggestive of a role in extracellular matrix (ECM) modeling. In summary, our data indicate that TAp73 regulates multiple metabolic pathways that impinge on numerous cellular functions, but that, overall, converge to sustain cell growth and proliferation

Developmental Regulation of an Adhesin Gene during Cellular Morphogenesis in the Fungal Pathogen Candida albicans

Peer reviewedPublisher PD

Stops making sense: translational trade-offs and stop codon reassignment

Background Efficient gene expression involves a trade-off between (i) premature termination of protein synthesis; and (ii) readthrough, where the ribosome fails to dissociate at the terminal stop. Sense codons that are similar in sequence to stop codons are more susceptible to nonsense mutation, and are also likely to be more susceptible to transcriptional or translational errors causing premature termination. We therefore expect this trade-off to be influenced by the number of stop codons in the genetic code. Although genetic codes are highly constrained, stop codon number appears to be their most volatile feature. Results In the human genome, codons readily mutable to stops are underrepresented in coding sequences. We construct a simple mathematical model based on the relative likelihoods of premature termination and readthrough. When readthrough occurs, the resultant protein has a tail of amino acid residues incorrectly added to the C-terminus. Our results depend strongly on the number of stop codons in the genetic code. When the code has more stop codons, premature termination is relatively more likely, particularly for longer genes. When the code has fewer stop codons, the length of the tail added by readthrough will, on average, be longer, and thus more deleterious. Comparative analysis of taxa with a range of stop codon numbers suggests that genomes whose code includes more stop codons have shorter coding sequences. Conclusions We suggest that the differing trade-offs presented by alternative genetic codes may result in differences in genome structure. More speculatively, multiple stop codons may mitigate readthrough, counteracting the disadvantage of a higher rate of nonsense mutation. This could help explain the puzzling overrepresentation of stop codons in the canonical genetic code and most variants

Sliding wear properties of HVOF thermally sprayed nylon-11 and nylon-11/ceramic composites on steel

Journal of Thermal Spray Technology, 16(5-6): pp. 927-932.Polymer and polymer/ceramic composite coatings were produced by ball-milling 60 μm Nylon- 11 together with nominal 10 vol.% of nano and multi-scale ceramic reinforcements and HVOF spraying these composite feedstocks onto steel substrates to produce semi-crystalline micron and nano-scale reinforced coatings polymer matrix composites. Room temperature dry sliding wear performance of pure Nylon-11, Nylon-11 reinforced with 7 nm silica, and multi-scale Nylon- 11/silica composite coatings incorporating 7-40 nm and 10 μm ceramic particles was characterized using a pin-on-disk tribometer. Coefficient of friction and wear rate were determined as a function of applied load and coating composition. Surface profilometry and scanning electron microscopy were used to characterize and analyze the coatings and wear scars. The pure Nylon-11 coating experienced less wear than the composites due to the occurrence of two additional wear mechanisms: abrasive and fatigue wear