University of Dundee

About: University of Dundee is a education organization based out in Dundee, United Kingdom. It is known for research contribution in the topics: Population & Protein kinase A. The organization has 19258 authors who have published 39640 publications receiving 1919433 citations. The organization is also known as: Universitas Dundensis & Dundee University.

Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases

Abstract: Parkinson’s disease is a degenerative disorder of the nervous system that affects approximately 1% of the elderly population. Mutations in the gene that encodes an enzyme known as LRRK2 are the most common causes of the inherited form of the disease. Such mutations generally increase the activity of LRRK2 and so drug companies have developed drugs that inhibit LRRK2 to prevent or delay the progression of Parkinson’s disease. However, it was not known what role LRRK2 plays in cells, and why its over-activation is harmful. Steger et al. used a 'proteomics' approach to find other proteins that are regulated by LRRK2. The experiments tested a set of newly developed LRRK2 inhibitors in cells and brain tissue from mice. The mice had mutations in the gene encoding LRRK2 that are often found in human patients with Parkinson’s disease. The experiments show that LRRK2 targets some proteins belonging to the Rab GTPase family, which are involved in transporting molecules and other 'cargoes' around cells. Several Rab GTPases are less active in the mutant mice, which interferes with the ability of these proteins to correctly direct the movement of cargo around the cell. Steger et al.’s findings will help to advance the development of new therapies for Parkinson’s disease. The next challenges are to identify how altering the activity of Rab GTPases leads to degeneration of the nervous system and how LRRK2 inhibitors may slow down these processes.

Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19.

Abstract: Background Coronavirus disease 2019 (COVID-19) can manifest as a viral-induced hyperinflammation with multiorgan involvement. Such patients often experience rapid deterioration and need for mechanical ventilation. Currently, no prospectively validated biomarker of impending respiratory failure is available. Objective We aimed to identify and prospectively validate biomarkers that allow the identification of patients in need of impending mechanical ventilation. Methods Patients with COVID-19 who were hospitalized from February 29 to April 9, 2020, were analyzed for baseline clinical and laboratory findings at admission and during the disease. Data from 89 evaluable patients were available for the purpose of analysis comprising an initial evaluation cohort (n = 40) followed by a temporally separated validation cohort (n = 49). Results We identified markers of inflammation, lactate dehydrogenase, and creatinine as the variables most predictive of respiratory failure in the evaluation cohort. Maximal IL-6 level before intubation showed the strongest association with the need for mechanical ventilation, followed by maximal CRP level. The respective AUC values for IL-6 and CRP levels in the evaluation cohort were 0.97 and 0.86, and they were similar in the validation cohort (0.90 and 0.83, respectively). The calculated optimal cutoff values during the course of disease from the evaluation cohort (IL-6 level > 80 pg/mL and CRP level > 97 mg/L) both correctly classified 80% of patients in the validation cohort regarding their risk of respiratory failure. Conclusion The maximal level of IL-6, followed by CRP level, was highly predictive of the need for mechanical ventilation. This suggests the possibility of using IL-6 or CRP level to guide escalation of treatment in patients with COVID-19–related hyperinflammatory syndrome.

Regulation of starvation- and virus-induced autophagy by the eIF2α kinase signaling pathway

Abstract: The eIF2alpha kinases are a family of evolutionarily conserved serine/threonine kinases that regulate stress-induced translational arrest. Here, we demonstrate that the yeast eIF2alpha kinase, GCN2, the target phosphorylation site of Gcn2p, Ser-51 of eIF2alpha, and the eIF2alpha-regulated transcriptional transactivator, GCN4, are essential for another fundamental stress response, starvation-induced autophagy. The mammalian IFN-inducible eIF2alpha kinase, PKR, rescues starvation-induced autophagy in GCN2-disrupted yeast, and pkr null and Ser-51 nonphosphorylatable mutant eIF2alpha murine embryonic fibroblasts are defective in autophagy triggered by herpes simplex virus infection. Furthermore, PKR and eIF2alpha Ser-51-dependent autophagy is antagonized by the herpes simplex virus neurovirulence protein, ICP34.5. Thus, autophagy is a novel evolutionarily conserved function of the eIF2alpha kinase pathway that is targeted by viral virulence gene products.

Fluoride varnishes for preventing dental caries in children and adolescents.

Abstract: BACKGROUND: Topically-applied fluoride varnishes have been used extensively as an operator-applied caries-preventive intervention for over three decades. This review updates the first Cochrane review of fluoride varnishes for preventing dental caries in children and adolescents, which was first published in 2002. OBJECTIVES: To determine the effectiveness and safety of fluoride varnishes in preventing dental caries in children and adolescents, and to examine factors potentially modifying their effect. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register (to 13 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 4), MEDLINE via OVID (1946 to 13 May 2013), EMBASE via OVID (1980 to 13 May 2013), CINAHL via EBSCO (1980 to 13 May 2013), LILACS and BBO via the BIREME Virtual Health Library (1980 to 13 May 2013), ProQuest Dissertations and Theses (1861 to 13 May 2013), and Web of Science Conference Proceedings (1945 to 13 May 2013). A search for ongoing trials was undertaken on ClinicalTrials.gov on 13 May 2013. There were no restrictions on language or date of publication in the search of the electronic databases. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials with blind outcome assessment used or indicated, comparing topically-applied fluoride varnish with placebo or no treatment in children up to 16 years during at least one year. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces in both permanent (D(M)FS) and primary (d(e/m)fs) teeth. DATA COLLECTION AND ANALYSIS: At least two review authors assessed all search results, extracted data and undertook risk of bias independently. Study authors were contacted for additional information. The primary measure of effect was the prevented fraction, that is the difference in mean caries increments between the treatment and control groups expressed as a percentage of the mean increment in the control group. The caries increments nearest to three years were used from each included study. Random-effects meta-analyses were performed where data could be pooled. Potential sources of heterogeneity were examined in random-effects meta-regression analyses. Adverse effects information was collected from the included trials. MAIN RESULTS: Twenty-two trials with 12,455 participants randomised (9595 used in analyses) were included. For the 13 that contributed data for the permanent tooth surfaces meta-analysis, the pooled D(M)FS prevented fraction estimate comparing fluoride varnish with placebo or no treatment was 43% (95% confidence interval (CI) 30% to 57%; P < 0.0001). There was substantial heterogeneity, confirmed statistically (P < 0.0001; I(2) = 75%), however this body of evidence was assessed as of moderate quality. The pooled d(e/m)fs prevented fraction estimate was 37% (95% CI 24% to 51%; P < 0.0001) for the 10 trials that contributed data for the primary tooth surfaces meta-analysis, also with some heterogeneity (P = 0.009; I(2) = 59%). Once again this body of evidence was assessed as of moderate quality. No significant association between estimates of D(M)FS or d(e/m)fs prevented fractions and the pre-specified factors of baseline caries severity, background exposure to fluorides, application features such as prior prophylaxis, concentration of fluoride, frequency of application were found. There was also no significant association between estimates of D(M)FS or d(e/m)fs prevented fractions and the post hoc factors: whether a placebo or no treatment control was used, length of follow-up, or whether individual or cluster randomisation was used, in the meta-regression models. A funnel plot of the trials in the main meta-analyses indicated no clear relationship between prevented fraction and study precision. In both methods, power is limited when few trials are included. There was little information concerning possible adverse effects or acceptability of treatment. AUTHORS' CONCLUSIONS: The conclusions of this updated review remain the same as those when it was first published. The review suggests a substantial caries-inhibiting effect of fluoride varnish in both permanent and primary teeth, however the quality of the evidence was assessed as moderate, as it included mainly high risk of bias studies, with considerable heterogeneity.

Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes

Abstract: We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.