Different responses to artificial ventilation in two stratified coastal basins

We studied the effects of pumping surface water down through the pycnocline (i.e. artificial ventilation) on hydrodynamics, oxygen concentrations, hydrogen sulfide, and nutrients in two anoxic coastal basins (Lannerstasundet and Sandofjarden). In addition, in a corresponding laboratory aquarium experiment, pumping of less saline surface water entrained dense bottom water with a mixing ratio of 6.8 and illustrated dispersal below the pycnocline. Oxygen saturation increased from 0 to 20%; oxygen penetrated poorly into the sediment of the aquarium. In the salinity-stratified Lannerstasundet basin, ventilation also oxidized the anoxic bottom water. The ventilation removed hydrogen sulfide and decreased the sub-pycnocline water pools of phosphorus and ammonium, which was not observed in a neighboring reference basin. The summertime ventilation warmed and made the sub-pycnocline water less saline. In the autumn, the inflows of cooled water from the surroundings with equal or higher salinity promoted its sinking in the relatively warm ventilated basin. The inflows maintained oxygen concentrations between 4 and 8 mg L-1 for months after the ventilation ended. In contrast to Lannerstasundet, ventilation did not prevent formation of anoxia and release of nutrients in the temperature stratified Sandofjarden. Here, the ventilation capacity was less than that in Lannerstasundet and ventilation expanded the sub-thermocline bottom area, warmed the bottom sediments, and probably displaced oxic water from the experimental area. The ventilation did not promote density conditions for inflows and no marked inflow-induced oxidation was observed after midsummer. We conclude that a significant amount of anoxic water was entrained into the ascending plume which reduced the oxygen content below the pycnocline ventilation in aquarium experiment. Additionally, summertime ventilation may improve the status of the salinity-stratified basins for further oxidation. The improvement occurs due to autumn cooling and favorable basin topography, which promote inflows of oxic water with larger density and thereby, renewal of bottom water in the pumped basin. The semi-enclosed and temperature-stratified basin cannot form such favorable density conditions for inflows and thus ventilation is less efficient.Peer reviewe

3 '-UTR poly(T/U) repeat of EWSR1 is altered in microsatellite unstable colorectal cancer with nearly perfect sensitivity

Approximately 15 % of colorectal cancers exhibit instability of short nucleotide repeat regions, microsatellites. These tumors display a unique clinicopathologic profile and the microsatellite instability status is increasingly used to guide clinical management as it is known to predict better prognosis as well as resistance to certain chemotherapeutics. A panel of five repeats determined by the National Cancer Institute, the Bethesda panel, is currently the standard for determining the microsatellite instability status in colorectal cancer. Recently, a quasimonomorphic mononucleotide repeat 16T/U at the 3' untranslated region of the Ewing sarcoma breakpoint region 1 gene was reported to show perfect sensitivity and specificity in detecting mismatch repair deficient colorectal, endometrial, and gastric cancers in two independent populations. To confirm this finding, we replicated the analysis in 213 microsatellite unstable colorectal cancers from two independent populations, 148 microsatellite stable colorectal cancers, and the respective normal samples by PCR and fragment analysis. The repeat showed nearly perfect sensitivity for microsatellite unstable colorectal cancer as it was altered in 212 of the 213 microsatellite unstable (99.5 %) and none of the microsatellite stable colorectal tumors. This repeat thus represents the first potential single marker for detecting microsatellite instability.Peer reviewe

GraphoGame - a catalyst for multi-level promotion of literacy in diverse contexts

GraphoGame (GG) is originally a technology-based intervention method for supporting children with reading difficulties. It is now known that children who face problems in reading acquisition have difficulties in learning to differentiate and manipulate speech sounds and consequently, in connecting these sounds to corresponding letters. GG was developed to provide intensive training in matching speech sounds and larger units of speech to their written counterparts. GG has been shown to benefit children with reading difficulties and the game is now available for all Finnish school children for literacy support. Presently millions of children in Africa fail to learn to read despite years of primary school education. As many African languages have transparent writing systems similar in structure to Finnish, it was hypothesized that GG-based training of letter-sound correspondences could also be effective in supporting children's learning in African countries. In this article we will describe how GG has been developed from a Finnish dyslexia prevention game to an intervention method that can be used not only to improve children's reading performance but also to raise teachers' and parents' awareness of the development of reading skill and effective reading instruction methods. We will also provide an overview of the GG activities in Zambia, Kenya, Tanzania, and Namibia, and the potential to promote education for all with a combination of scientific research and mobile learning.Peer reviewe

Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

Approximately 15% of colorectal cancers exhibit microsatellite instability (MSI), which leads to accumulation of large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in micro-satellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. To identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI colorectal cancers revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI colorectal cancers. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase AASDH and the solute transporter SLC9A8. Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in colorectal cancer. (C) 2017 AACR.Peer reviewe

Dietary energy substrates reverse early neuronal hyperactivity in a mouse model of Alzheimer's disease

Deficient energy metabolism and network hyperactivity are the early symptoms of Alzheimer's disease (AD). In this study, we show that administration of exogenous oxidative energy substrates (OES) corrects neuronal energy supply deficiency that reduces the amyloid-beta-induced abnormal neuronal activity in vitro and the epileptic phenotype in AD model in vivo. In vitro, acute application of protofibrillar amyloid-142 (A142) induced aberrant network activity in wild-type hippocampal slices that was underlain by depolarization of both the neuronal resting membrane potential and GABA-mediated current reversal potential. A142 also impaired synaptic function and long-term potentiation. These changes were paralleled by clear indications of impaired energy metabolism, as indicated by abnormal NAD(P)H signaling induced by network activity. However, when glucose was supplemented with OES pyruvate and 3-beta-hydroxybutyrate, A142 failed to induce detrimental changes in any of the above parameters. We administered the same OES as chronic supplementation to a standard diet to APPswe/PS1dE9 transgenic mice displaying AD-related epilepsy phenotype. In the ex-vivo slices, we found neuronal subpopulations with significantly depolarized resting and GABA-mediated current reversal potentials, mirroring abnormalities we observed under acute A1-42 application. Ex-vivo cortex of transgenic mice fed with standard diet displayed signs of impaired energy metabolism, such as abnormal NAD(P)H signaling and strongly reduced tolerance to hypoglycemia. Transgenic mice also possessed brain glycogen levels twofold lower than those of wild-type mice. However, none of the above neuronal and metabolic dysfunctions were observed in transgenic mice fed with the OES-enriched diet. In vivo, dietary OES supplementation abated neuronal hyperexcitability, as the frequency of both epileptiform discharges and spikes was strongly decreased in the APPswe/PS1dE9 mice placed on the diet. Altogether, our results suggest that early AD-related neuronal malfunctions underlying hyperexcitability and energy metabolism deficiency can be prevented by dietary supplementation with native energy substrates. Read the Editorial Highlight for this article on doi: 10.1111/jnc.12138.</p

Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata

Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.Peer reviewe

Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Abstract Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P &lt;5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate&lt;0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD