The role of caspases in Parkinson’s Disease pathogenesis: a brief look at the mitochondrial pathway

Parkinson’s disease (PD) is a neurodegenerative disorder characterised by tremor, rigidity, Bradykinesia and reduced facial expression. Development of PD is considered to be the result of deficiency of the neurotransmitter dopamine, which is due to death of Dopamine-Containing Neurons (DCNs) that produce dopamine in the pars compacta region of the substantia nigra. Although the concentrated efforts of the scientific community over the last decades, the etiology of the death of DCN is yet to be understood. Oxidative stress has been considered as one of the causes of defects in the mitochondria leading to the dopaminergic cell damage [1]. Levodopa therapy is a well-known treatment for the symptoms of PD, however long term use of L-dopa causes side effects including further enhancement of oxidative stress [2]. The elevated levels of Reactive Oxidative Species (ROS) such as hydrogen peroxide, superoxide and hydroxyl ions, induce stimulation to the Permeability Transition Pore (mPTP) of the mitochondria leading to the collapse of the mitochondrial membrane potential and the release of cytochrome C. Furthermore, increased ROS activity promote nitric oxide binding to superoxide producing peroxynitrate enhancing oxidative and nitrosative stress, which results in DNA damage, chromosomal mutations, lipid peroxidation and enzyme defects [3]. Mutation of E3 ligase caused by peroxynitrate damage leads to impairment of ubiquitin-proteasome system, resulting in high levels of defective proteins, which accumulate in the Endoplasmic Reticulum (ER) promoting ER stress and ultimately cell death. Moreover, the apoptotic neuron triggers injury signals that activate microglia and promote release of cytokines such as interleukins-6 and -8. Subsequently, interleukins trigger Caspase activation along with inducible NO synthase, which further elevates formation of nitric oxide. Exposure to excessive reactive nitrite species along with enhanced production of ROS and peroxynitrate lead to dysfunction of complex-IV and complex-I activities of the mitochondria and promote mitochondrialmediated apoptosis through Caspase activation [4,5]

Characteristics of Pro-c Analogies and Blends between Research Publications

Dr Inventor is a tool that aims to enhance the professional (Pro-c) creativity of researchers by suggesting novel hypotheses, arising from analogies between publications. Dr Inventor processes original research documents using a combination of lexical analysis and cognitive computation to identify novel comparisons that suggest new research hypotheses, with the objective of supporting a novel research publication. Research on analogical reasoning strongly suggests that the value of analogy-based comparisons depends primarily on the strength of the mapping (or counterpart projection) between the two analogs. An evaluation study of a number of computer generated comparisons attracted creativity ratings from a group of practising researchers. This paper explores a variety of theoretically motivated metrics operating on different conceptual spaces, identifying some weak associations with user's creativity ratings. Surprisingly, our results show that metrics focused on the mapping appear to have less relevance to creativity than metrics assessing the inferences (blended space). This paper includes a brief description of a research project currently exploring the best research hypothesis generated during this evaluation. Finally, we explore PCA as a means of specifying a combined multiple metrics from several blending spaces as a basis for detecting comparisons to enhance researchers’ creativity

Cancer treatment associated cardiac toxicities

Cardiovascular disease remains the leading cause of mortality and morbidity in men and women both in the US and worldwide. With increased access to healthcare, it is predicted that life expectancies in developed countries will continue to rise and thus, lead to an increase in both cardiovascular disease and cancer. Similarly, improved survival rates in cancer patients have led to an increased awareness of the presence and potential worsening of cardiovascular disease in these patients. Cardiovascular complications due to side effects from cancer therapy or from cancer progression can be a common occurrence. Although recent advances in cancer therapeutics have led to improved survival rates and quality of life, the increase in life expectancy may be counteracted by the increased morbidity and mortality from progressive cardiac pathology. Examples of such complications include local invasion or distant metastatic spread, which can lead to superior vena cava syndrome, cardiac tamponade, or hyperviscosity syndromes. In addition, many chemo and radiation therapies can be directly toxic to the cardiovascular system. This review aims to discuss the potential cardiac toxicities of the most commonly used chemotherapeutics along with some strategies to manage these complex patients

Survey on awareness and preference of ceramic bracket debonding techniques among orthodontists

The objectives of this study was to evaluate the awareness of different ceramic bracket debonding techniques among orthodontists in the USA and the most commonly used debonding technique for ceramic bracket removal. A survey on preference for debonding and awareness of debonding techniques was emailed to 2,227 members of the American Association of Orthodontists (AAO). 119 orthodontists completed the survey. 111 responses were included in the study analysis of ceramic bracket users. The most common technique used was mechanical debonding. 86.5% used a specially designed bracket removing plier from the manufacturer. Overall, there were 59.5% of surveyed orthodontists who were aware of electrothermal debonding, 73% were unaware of ultrasonic debonding and 83.8% were unaware of laser debonding. There were more orthodontists with an affiliation with an academic institution aware of electrothermal debonding (p=0.002). There also was a trend of orthodontists having no affiliation with an institution who were unaware of laser debonding (p=0.015). This survey showed that the majority of orthodontists who responded to the questionnaire were unaware of alternative debonding techniques of ceramic brackets. All orthodontists who use ceramic brackets utilized mechanical debonding technique

Gold nanoparticle decorated single walled carbon nanotube nanocomposite with synergistic peroxidase like activity for D-alanine detection

© The Royal Society of Chemistry. In this report, a gold nanoparticle decorated single walled carbon nanotube (SWCNTs) nanocomposite was shown to possess synergistic intrinsic peroxidase like activity and enhanced affinity towards H2O2 oxidation. The gold nanoparticle decorated SWCNTs nanocomposite was characterized by high catalytic activity, enhanced stability from the gold nanoparticles and improved dispersion from the SWCNTs. Subsequently, this nanocomposite was proved to be a novel peroxidase mimetic with great potential to catalyze the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) in the presence of H2O2 to yield a blue colored product. As a proof of concept, the gold nanoparticle decorated SWCNTs composite was used as a robust nanoprobe for the detection of d-alanine with improved analytical characteristics. Taking into account the valuable intrinsic peroxidase activity of the nanohybrid, the present work may find widespread applications in the field of sensors and biosensors for diverse applications. This journal i

Ifit1 regulates norovirus infection and enhances the interferon response in murine macrophage-like cells [version 1; peer review: 1 approved, 2 approved with reservations]

Background: Norovirus, also known as the winter vomiting bug, is the predominant cause of non-bacterial gastroenteritis worldwide. Disease control is predicated on a robust innate immune response during the early stages of infection. Double-stranded RNA intermediates generated during viral genome replication are recognised by host innate immune sensors in the cytoplasm, activating the strongly antiviral interferon gene programme. Ifit proteins (interferon induced proteins with tetratricopeptide repeats), which are highly expressed during the interferon response, have been shown to directly inhibit viral protein synthesis as well as regulate innate immune signalling pathways. Ifit1 is well-characterised to inhibit viral translation by sequestration of eukaryotic initiation factors or by directly binding to the 5' terminus of foreign RNA, particularly those with non-self cap structures. However, noroviruses have a viral protein, VPg, covalently linked to the 5' end of the genomic RNA, which acts as a cap substitute to recruit the translation initiation machinery. Methods: : Ifit1 knockout RAW264.7 murine macrophage-like cells were generated using CRISPR-Cas9 gene editing. These cells were analysed for their ability to support murine norovirus infection, determined by virus yield, and respond to different immune stimuli, assayed by quantitative PCR. The effect of Ifit proteins on norovirus translation was also tested in vitro . Results: : Here, we show that VPg-dependent translation is completely refractory to Ifit1-mediated translation inhibition in vitro and Ifit1 cannot bind the 5' end of VPg-linked RNA. Nevertheless, knockout of Ifit1 promoted viral replication in murine norovirus infected cells. We then demonstrate that Ifit1 promoted interferon-beta expression following transfection of synthetic double-stranded RNA but had little effect on toll-like receptor 3 and 4 signalling. Conclusions: : Ifit1 is an antiviral factor during norovirus infection but cannot directly inhibit viral translation. Instead, Ifit1 stimulates the antiviral state following cytoplasmic RNA sensing, contributing to restriction of norovirus replication

Solid weak BCC-algebras

We characterize weak BCC-algebras in which the identity $(xy)z=(xz)y$ is satisfied only in the case when elements $x,y$ belong to the same branch

Moving beyond DNA sequence to improve plant stress responses

Plants offer a habitat for a range of interactions to occur among different stress factors. Epigenetics has become the most promising functional genomics tool, with huge potential for improving plant adaptation to biotic and abiotic stresses. Advances in plant molecular biology have dramatically changed our understanding of the molecular mechanisms that control these interactions, and plant epigenetics has attracted great interest in this context. Accumulating literature substantiates the crucial role of epigenetics in the diversity of plant responses that can be harnessed to accelerate the progress of crop improvement. However, harnessing epigenetics to its full potential will require a thorough understanding of the epigenetic modifications and assessing the functional relevance of these variants. The modern technologies of profiling and engineering plants at genome-wide scale provide new horizons to elucidate how epigenetic modifications occur in plants in response to stress conditions. This review summarizes recent progress on understanding the epigenetic regulation of plant stress responses, methods to detect genome-wide epigenetic modifications, and disentangling their contributions to plant phenotypes from other sources of variations. Key epigenetic mechanisms underlying stress memory are highlighted. Linking plant response with the patterns of epigenetic variations would help devise breeding strategies for improving crop performance under stressed scenarios