Month: February 2020

Concluded that there was little evidence that women intending to be pregnant were more likely to engage in positive health behaviours. The high level of pregnancy planning in our study is in keeping with other data from the UK when LMUP scores are compared across similar age groups. Use of the LMUP in a number of high throughput screening inhibitor studies shows that around two thirds of pregnancies leading to births in the UK are planned ; therefore a majority of women who give birth are in a position to benefit from the direct targeting of pre-pregnancy care. Other studies have reported low awareness among women or reproductive age about folic acid and the conditions that it can prevent Our study indicates that engagement between women and health professionals about preconception health and care is often lacking leading to multiple missed opportunities to improve maternal and child health. There is specific guidance for professionals on pre-pregnancy care relating to conditions such as diabetes, epilepsy and obesity,but more general guidance on pre-pregnancy health and care does not seem to be reaching the right settings. Guidelines alone are not sufficient to change professional behaviour. Preconception health does not fall neatly within a particular medical specialty and despite guidance there is no standardised provision of care in the UK which may explain why responsibility for providing preconception care appears confused and delivery patchy. Another reason may be the lack of studies showing clear benefits of interventions starting before pregnancy on birth outcomes, or how to implement such interventions effectively. Such studies are challenging as they need to identify women before conception. A recent study of barriers to the implementation of preconception care by general practitioners in Australia concluded that lack of time was the biggest barrier. Other barriers were similar to those reported here including women not presenting at the preconception stage, competing preventive care issues, the cost associated with extending consultations to include preconception care and the lack of appropriate resources. Perceived facilitators to delivery of care included checklists, patient leaflets, waiting room posters and the availability of preconception care consultations. Awareness of preconception health issues, pregnancy planning and uptake of interventions before pregnancy care are related but distinct issues. All three are required to improve preconception health and pregnancy outcomes. In our study, women who received health professional input did not have greater educational attainment than women with no health professional input; they were more likely to have a relevant medical condition, and more likely to adopt positive behaviour changes. Together these findings suggest that focusing on pre-pregnancy intervention by health professionals would not merely benefit the women with specific medical disorders, but could be an effective approach to addressing important health inequalities relating to smoking, alcohol and other risk behaviours.

Small ubiquitin-like modifier proteins are members of the ubiquitin-like protein family. Covalent modification of proteins by SUMO affects their activity, intracellular localization, stability, and interaction with other proteins and DNA. The cellular Reversine SUMOylation pathway, which is largely analogous to the ubiquitin modification pathway, regulates many important cellular processes. In brief, SUMO precursors are C-terminally processed to create an active form, which is activated by the formation of a thioester bond between the C-terminal glycine residue of SUMO and the active cysteine reside of a heterodimeric E1 activation enzyme, which comprises SAE1 and SAE2. SUMO is then transferred to the E2 conjugation enzyme, Ubc9, via an analogous thioester bond, and finally to the lysine residue of a substrate. SUMO E3 ligases, such as PIAS proteins, RanBP2, and Pc2, help transfer SUMO from Ubc9 to the substrate. Both Ubc9 and the E3 ligases appear to control the substrate specificity of SUMOylation. SUMO can be released from a substrate through cleavage by proteases called SENP; therefore, SUMOylation is reversible. Proteins also can interact with SUMO non-covalently through a SUMO-interacting motif, which is characterized by a stretch of hydrophobic residues, often flanked by acidic residues. Evidence is accumulating that the cellular SUMOylation pathway plays a regulatory role in infection by many different viruses, including human cytomegalovirus . HCMV is an opportunistic pathogen that can cause congenital disease and produces serious disease complications in immunocompromised individuals. During the lytic cycle of HCMV infection, viral genes are expressed in a cascade fashion with immediate-early, early, and late phases. The 72-kDa IE1 and 86-kDa IE2 proteins are the major IE proteins that regulate activation of viral genes and modulate host cell functions. Both IE1 and IE2 are modified by SUMO during HCMV infection. IE2 is a strong transactivator that interacts with numerous cellular transactivators and is essential for early and late viral gene expression. IE2 is modified by SUMO at two lysine residues, K175 and K180. In transfection assays, SUMOylation of IE2 enhances the transactivation of diverse cellular and viral promoters by IE2. Consistently, transactivation activity of IE2 has been correlated with its degree of SUMOylation. IE2 directly binds to Ubc9 and PIAS1. Mutation of both K175 and K180 in a laboratory strain and a clinical isolate caused a modest decrease in virus replication, indicating that IE2 SUMOylation promotes the virus lytic cycle in the context of virus infection. However, the effect of IE2 SUMOylation on viral growth appears to depend on the virus strains and infection conditions, since similar mutations in another laboratory strain did not significantly affect viral growth. IE2 also non-covalently interacts with SUMO through a SIM adjacent to the SUMO conjugation sites. This SIM is necessary for efficient SUMOylation and transactivation activity of IE2, thereby promoting viral growth.

Moreover, oxaliplatin repeated treatment induces severe peripheral neuropathy that can affect approximately 50% of the patients receiving cumulative doses higher than 1000 mg/m2. Anti-hyperalgesic compounds currently used to treat chemotherapy-induced pain, like antiepileptics or antidepressant, are weakly effective. The therapeutic failure reflects the lack of knowledge about the molecular bases of neuropathies. In a rat model of oxaliplatin-induced neuropathy we previously identified oxidative stress as a main biomolecular dysfunction showing a relationship between oxidative damage of the nervous system and pain. The “oxidative hypothesis” was confirmed in primary cultures of astrocytes, a glial cell type activated in vivo by oxaliplatin treatment. Since oxaliplatin does not possess direct oxidative properties, redox unbalance seems due to a cellmediated effect able to alter the oxidative machinery. After oxaliplatin treatment, mitochondria are modified in morphology and impaired in function. Less inquired is the role of the other intracellular organelle strongly implied in redox processes: the peroxisome. Peroxisomes are the last among the subcellular organelles to be identified. The discovery of the co-localization of catalase with H2O2-generating oxidases in peroxisomes was the first indication of their involvement in the metabolism of oxygen metabolites. The high peroxisomal consumption of O2, the demonstration of the production of H2O2, O22 and more recently of ?NO, as well as the discovery of several ROS metabolizing enzymes in peroxisomes has supported the notion that these ubiquitous organelles play a key role in both the production and scavenging of ROS in the cell. In the nervous system, the functional relevance of these organelles is dramatically highlighted by peroxisomal disorders. Severe demyelination, axonal degeneration and neuroinflammation are induced by genetic deficit of peroxisome. Moreover, peroxisomes were recently involved in the development and progression of specific degenerative diseases. In mouse liver was originally CPI-613 cloned a nuclear receptor subfamily of ligand-activated transcription factors, the Peroxisome Proliferator-Activated Receptors . PPARs may activate genes with a PPAR response element in their promoter regions. Girnun et al. highlighted that PPARc stimulation increases the expression and activity of catalase, a heme-containing peroxisomal enzyme that breaks down hydrogen peroxide to water and oxygen. Recently, agonists of the c subtype of PPARs received considerable attention as potential therapeutic agents for a wide range of neurological diseases, including neurodegenerative diseases, traumatic injuries, stroke and demyelinating diseases. Aimed to characterize the oxaliplatin neurotoxicity, we studied the peroxisome-related signal in vitro, in astrocyte cell culture, and in vivo in a rat model. Peroxisome stimulation by the PPARc agonist rosiglitazone was analyzed to individuate new possible pharmacological.

Apart from being involved in the formation and maintenance of skeletal muscles, bones and the placenta, cell-to-cell fusion plays an important role in numerous other biological processes like fertilization. It has also been implicated in the initiation and progression of cancer and as a driving force in evolution. Moreover, cell-to-cell fusion has been of great value to establish the chromosomal location of specific genes, can be used to induce cellular reprogramming and is indispensable for Oligomycin A generating hybridomas. The involvement of cell-to-cell fusion in a large variety of biological processes and its diverse biotechnological applications have prompted investigations into the mechanisms of cell fusion and the contribution of specific factors to this process. Instrumental to this research is the availability of robust assays to determine cell fusion kinetics and extent. However, most of the existing quantitative cell fusion assays do not allow consecutive analysis of the same cells/tissue. Accordingly, in this paper a new quantitative assay is presented to monitor cell-to-cell fusion. This assay is based on the activation of a latent GpLuc gene after fusion of cells containing this latent reporter gene with cells encoding a recombinase that activates the dormant GpLuc gene. The extent of cell-to-cell fusion is subsequently quantified by simply measuring the enzymatic activity of the luciferase molecules secreted by the cellular fusion products. To the best of our knowledge this is the first assay that allows quantification of cell fusion activity by medium sampling. To validate the new cell fusion assay it was used to monitor the formation of myotubes/sacs in cultures of serum-deprived human myoblasts. In these experiments, several parameters were varied including the acceptor-to-donor cell ratio and the sample regimen of the cell culture medium. Increased serum levels of reactive carbonyl species, such as methylglyoxal, are present in several pathologies and cause complications in severe conditions and diseases, like diabetes mellitus, cardiovascular diseases, atherosclerosis, hypertension, metabolic syndrome, obesity, psoriasis, aging Alzheimer’s disease , dementias, and other neurobiological diseases. Methylglyoxal is a highly reactive a-oxoaldehyde with strong oxidant and glycation properties. Its immediate elimination by detoxification systems is crucial. Accumulated methylglyoxal reacts with proteins, DNA and other biomolecules causing inhibition of enzyme activity, transcriptional activation, apoptosis. The end products of the reactions between methylgyoxal and free amino groups of molecules are insoluble protease-resistant polymers . Methylglyoxal triggers carbonyl and oxidative stress and activates a series of inflammatory responses leading to accelerated vascular endothelial damage. Based on data obtained on peripheral endothelial cells, which forms the blood-brain barrier was also investigated. A concentration-dependent cell toxicity and barrier dysfunction was recently described on a brain endothelial cell line.

These studies have concluded that performance on tasks of memory known to rely on the medial temporal lobes develops during early childhood. However, performance on tasks of executive functions, such as problem solving and strategy use, continues to develop through childhood and into adolescence. Further evidence of the role of memory and executive functions in visual associate learning, as well as their differential developmental rates, was provided by modulating the difficulty level of a visual associate Torin 1 learning task in children aged 5-12 years old. The NBMT-CV included both an exposure trial during which the children were exposed to the to-be-remembered objects followed by learning trials of increasing task difficulty during which the children learned the object-location associations. At the lower difficulty level, no differences were noted between age groups. Conversely, 5-6 year olds consistently performed more poorly than the older children at the higher difficulty level. This was interpreted to indicate that memory was largely developed by 5-6 years old while differences in performance between age groups at the higher difficulty level were attributable to continued development of executive functions. In sum, the CPAL is a novel measure of visual paired associate learning that allows for the classification of different types of errors made during learning. This allows for the measurement of different cognitive processes, in particular memory and executive functions. Additionally, by varying the memory load of the task, it is also possible to obtain an estimate of working memory capacity. The CPAL is the first task that allows for the investigation of the different component processes of associate learning within the same task. Therefore, our study is the first to provide an understanding of how maturation in memory, executive functions and working memory capacity operate to form the foundation for maturation in visual paired associate learning. These data also provide neuropsychologists and psychologists with new information that can assist with their interpretation of poor visual associate learning in school aged children. Several limitations of this study should be acknowledged. First, although the current data indicate that changes in performance on visual paired associate learning tasks through early to middle childhood are influenced by cognitive processes that have different developmental trajectories, a prospective study is needed to fully elucidate the developmental course of these cognitive processes. Second, in order to establish the validity of the CPAL as a measure of associate learning in children, it is necessary to examine the extent to which wellvalidated neuropsychological measures of memory correlate with performance on the CPAL, as well as how children with memory disorders perform on this task. Studies examining performance on the CPAL in older adults with MCI or AD and in healthy adults challenged.