Inhibition of alcohol dehydrogenases by thiol compounds

2-Mercaptoethanol is a strong inhibitor of LADH. The inhibitory effect is likely due to the binding of the SH group to the enzymatic zinc ion. Various thiol compounds do not inhibit YADH and it is suggested that the zinc atoms involved in the catalytic mechanism of LADH and YADH may have different structural arrangements and that these zinc atoms in YADH may not be blocked by thiol compounds. Thiol compounds also quench the enhanced fluorescence of LADH-NADH in a pH-dependent manner. At pH 9.2, the binding of coenzyme to LADH is replaced by 2-mercaptoethanol, whilst at pH 7.3, it further quenches the fluorescence of NADH-LADH. This quenching of fluorescence is likely attributed to a conformational change and energy transfer upon binding of 2-mercaptoethanol to the LADH-NADH complex. Complete reversal of the inhibitory effect of thiol compounds on LADH can be obtained by dialysis.     

Water quality assessment using diatom assemblages and advanced modelling techniques

1. Two types of artificial neural networks procedures were used to define and predict diatom assemblage structures in Luxembourg streams using environmental data. 2. Self‐organising maps (SOM) were used to classify samples according to their diatom composition, and multilayer perceptron with a backpropagation learning algorithm (BPN) was used to predict these assemblages using environmental characteristics of each sample as input and spatial coordinates (X and Y) of the cell centres of the SOM map identified as diatom assemblages as output. Classical methods (correspondence analysis and clustering analysis) were then used to identify the relations between diatom assemblages and the SOM cell number. A canonical correspondence analysis was also used to define the relationship between these assemblages and the environmental conditions. 3. The diatom‐SOM training set resulted in 12 representative assemblages (12 clusters) having different species compositions. Comparison of observed and estimated sample positions on the SOM map were used to evaluate the performance of the BPN (correlation coefficients were 0.93 for X and 0.94 for Y). Mean square errors of 12 cells varied from 0.47 to 1.77 and the proportion of well predicted samples ranged from 37.5 to 92.9%. This study showed the high predictability of diatom assemblages using physical and chemical parameters for a small number of river types within a restricted geographical area.     

Effects of wind‐driven spatial structure and environmental heterogeneity on high‐altitude wetland macroinvertebrate assemblages with contrasting dispersal modes

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Biallelic Variants in TTLL5, Encoding a Tubulin Glutamylase,Cause Retinal Dystrophy

In a subset of inherited retinal degenerations (including cone, cone-rod, and macular dystrophies), cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders. To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with “cone-first” retinal disease and clinical features atypical for ABCA4 retinopathy. We then conducted a gene-based case-control association study with an internal exome data set as the control group. TTLL5, encoding a tubulin glutamylase, was highlighted as the most likely disease-associated gene; 2 of 28 affected subjects harbored presumed loss-of-function variants: c.[1586_1589delAGAG];[1586_1589delAGAG], p.[Glu529Valfs^∗2];[Glu529Valfs^∗2], and c.[401delT(;)3354G>A], p.[Leu134Argfs^∗45(;)Trp1118^∗]. We then inspected previously collected exome sequence data from individuals with related phenotypes and found two siblings with homozygous nonsense variant c.1627G>T (p.Glu543^∗) in TTLL5. Subsequently, we tested a panel of 55 probands with retinal dystrophy for TTLL5 mutations; one proband had a homozygous missense change (c.1627G>A [p.Glu543Lys]). The retinal phenotype was highly similar in three of four families; the sibling pair had a more severe, early-onset disease. In human and murine retinae, TTLL5 localized to the centrioles at the base of the connecting cilium. TTLL5 has been previously reported to be essential for the correct function of sperm flagella in mice and play a role in polyglutamylation of primary cilia in vitro. Notably, genes involved in the polyglutamylation and deglutamylation of tubulin have been associated with photoreceptor degeneration in mice. The electrophysiological and fundus autofluorescence imaging presented here should facilitate the molecular diagnosis in further families.     

The Spontaneously Adhesive Leukocyte Function-associated Antigen-1 (LFA-1) Integrin in Effector T Cells Mediates Rapid Actin- and Calmodulin-dependent Adhesion Strengthening to Ligand under Shear Flow

Integrins in effector T cells are highly expressed and important for trafficking of these cells and for their effector functions. However, how integrins are regulated in effector T cells remains poorly characterized. Here, we have investigated effector T cell leukocyte function-associated antigen-1 (LFA-1) regulation in primary murine effector T cells. These cells have high LFA-1 integrin expression and display high spontaneous binding to intercellular adhesion molecule-1 (ICAM-1) ligand under static conditions. In addition, these cells are able to migrate spontaneously on ICAM-1. Atomic force microscopy measurements showed that the force required for unbinding of integrin-ligand interactions increases over time (0.5–20-s contact time). The maximum unbinding force for this interaction was ∼140 piconewtons at 0.5-s contact time, increasing to 580 piconewtons at 20-s contact time. Also, the total work required to disrupt the interaction increased over the 20-s contact time, indicating LFA-1-mediated adhesion strengthening in primary effector T cells over a very quick time frame. Effector T cells adhered spontaneously to ICAM-1 under conditions of shear flow, in the absence of chemokine stimulation, and this binding was independent of protein kinase B/Akt and protein kinase C kinase activity, but dependent on calcium/calmodulin signaling and an intact actin cytoskeleton. These results indicate that effector T cell integrins are highly expressed and spontaneously adhesive in the absence of inside-out integrin signaling but that LFA-1-mediated firm adhesion under conditions of shear flow requires downstream integrin signaling, which is dependent on calcium/calmodulin and the actin cytoskeleton.     

Analysis of macrobenthic communities in Flanders,Belgium, using a stepwise input variable selection procedure with artificial neural networks

The effect of environmental conditions on river macrobenthic communities was studied using a dataset consisting of 343 sediment samples from unnavigable watercourses in Flanders, Belgium. Artificial neural network models were used to analyse the relation among river characteristics and macrobenthic communities. The dataset included presence or absence of macroinvertebrate taxa and 12 physicochemical and hydromorphological variables for each sampling site. The abiotic variables served as input for the artificial neural networks to predict the macrobenthic community. The effects of the input variables on model performance were assessed in order to identify the most diagnostic river characteristics for macrobenthic community composition. This was done by consecutively eliminating the least important variables and, when beneficial for model performance, adding previously removed ones again. This stepwise input variable selection procedure was tested not only on a model predicting the entire macrobenthic community, but also on three models, each predicting an individual taxon. Additionally, during each step of the stepwise leave-one-out procedure, a sensitivity analysis was performed to determine the response of the predicted macroinvertebrate taxa to the input variables applied. This research illustrated that a combination of input variable selection with sensitivity analyses can contribute to the development of reliable and ecologically relevant ANN models. The river characteristics predicting presence or absence of the benthic macroinvertebrates best were the Julian day, conductivity, and dissolved oxygen content. These conditions reflect the importance of discharges of untreated wastewater that occurred during the period of investigation in nearly all Flemish rivers.     

Applications of artificial neural networks predicting macroinvertebrates in freshwaters

To facilitate decision support in freshwater ecosystem protection and restoration management, habitat suitability models can be very valuable. Data driven methods such as artificial neural networks (ANNs) are particularly useful in this context, seen their time-efficient development and relatively high reliability. However, specialized and technical literature on neural network modelling offers a variety of model development criteria to select model architecture, training procedure, etc. This may lead to confusion among ecosystem modellers and managers regarding the optimal training and validation methodology. This paper focuses on the analysis of ANN development and application for predicting macroinvertebrate communities, a species group commonly used in freshwater assessment worldwide. This review reflects on the different aspects regarding model development and application based on a selection of 26 papers reporting the use of ANN models for the prediction of macroinvertebrates. This analysis revealed that the applied model training and validation methodologies can often be improved and moreover crucial steps in the modelling process are often poorly documented. Therefore, suggestions to improve model development, assessment and application in ecological river management are presented. In particular, data pre-processing determines to a high extent the reliability of the induced models and their predictive relevance. This also counts for the validation criteria, that need to be better tuned to the practical simulation requirements. Moreover, the use of sensitivity methods can help to extract knowledge on the habitat preference of species and allow peer-review by ecological experts. The selection of relevant input variables remains a critical challenge as well. Model coupling is a missing crucial step to link human activities, hydrology, physical habitat conditions, water quality and ecosystem status. This last aspect is probably the most valuable aspect to enable decision support in water management based on ANN models.     

Association of Maternal Vitamin D Status with Glucose Tolerance and Caesarean Section in a Multi-Ethnic Asian Cohort: The Growing Up in Singapore Towards Healthy Outcomes Study

Objective

Epidemiological studies relating maternal 25-hydroxyvitamin D (25OHD) with gestational diabetes mellitus (GDM) and mode of delivery have shown controversial results. We examined if maternal 25OHD status was associated with plasma glucose concentrations, risks of GDM and caesarean section in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study.

Methods

Plasma 25OHD concentrations, fasting glucose (FG) and 2-hour postprandial glucose (2HPPG) concentrations were measured in 940 women from a Singapore mother-offspring cohort study at 26–28 weeks’ gestation. 25OHD inadequacy and adequacy were defined based on concentrations of 25OHD ≤75nmol/l and >75nmol/l respectively. Mode of delivery was obtained from hospital records. Multiple linear regression was performed to examine the association between 25OHD status and glucose concentrations, while multiple logistic regression was performed to examine the association of 25OHD status with risks of GDM and caesarean section.

Results

In total, 388 (41.3%) women had 25OHD inadequacy. Of these, 131 (33.8%), 155 (39.9%) and 102 (26.3%) were Chinese, Malay and Indian respectively. After adjustment for confounders, maternal 25OHD inadequacy was associated with higher FG concentrations (β = 0.08mmol/l, 95% Confidence Interval (CI) = 0.01, 0.14), but not 2HPPG concentrations and risk of GDM. A trend between 25OHD inadequacy and higher likelihood of emergency caesarean section (Odds Ratio (OR) = 1.39, 95% CI = 0.95, 2.05) was observed. On stratification by ethnicity, the association with higher FG concentrations was significant in Malay women (β = 0.19mmol/l, 95% CI = 0.04, 0.33), while risk of emergency caesarean section was greater in Chinese (OR = 1.90, 95% CI = 1.06, 3.43) and Indian women (OR = 2.41, 95% CI = 1.01, 5.73).

Conclusions

25OHD inadequacy is prevalent in pregnant Singaporean women, particularly among the Malay and Indian women. This is associated with higher FG concentrations in Malay women, and increased risk of emergency caesarean section in Chinese and Indian women.