A high-dimensional mediation model for a neuroimaging mediator: Integrating clinical,neuroimaging, and neurocognitive data to mitigate late effects in pediatric cancer

Pediatric cancer treatment, especially for brain tumors, can have profound and complicated late effects. With the survival rates increasing because of improved detection and treatment, a more comprehensive understanding of the impact of current treatments on neurocognitive function and brain structure is critically needed. A frontline medulloblastoma clinical trial (SJMB03) has collected data, including treatment, clinical, neuroimaging, and cognitive variables. Advanced methods for modeling and integrating these data are critically needed to understand the mediation pathway from the treatment through brain structure to neurocognitive outcomes. We propose an integrative Bayesian mediation analysis approach to model jointly a treatment exposure, a high-dimensional structural neuroimaging mediator, and a neurocognitive outcome and to uncover the mediation pathway. The high-dimensional imaging-related coefficients are modeled via a binary Ising–Gaussian Markov random field prior (BI-GMRF), addressing the sparsity, spatial dependency, and smoothness and increasing the power to detect brain regions with mediation effects. Numerical simulations demonstrate the estimation accuracy, power, and robustness. For the SJMB03 study, the BI-GMRF method has identified white matter microstructure that is damaged by cancer-directed treatment and impacts late neurocognitive outcomes. The results provide guidance on improving treatment planning to minimize long-term cognitive sequela for pediatric brain tumor patients.     

Hope for the White-headed Duck,Oxyura leucocephala (Aves: Anatidae) in Turkey despite a declining breeding population and abandonment of its traditional wintering area?

The development of the breeding and non-breeding populations of the White-headed Duck, Oxyura leucocephala, in Turkey was analysed based on all available records from the period 1966–2016 from 99 different areas. Breeding is confined to Inner Anatolia and the eastern parts of the country. The breeding population had been estimated as 200–250 pairs in the period 1996–2001 but recent observations show that it does now not exceed 80–125 pairs which is a decline of about 50% within two decades. The non-breeding winter population comprises approximately 8,500–10,000 individuals. Burdur Lake has traditionally housed more than 90% of the population but is no longer a significant resting place. The numbers started to decrease from more than 10,000 birds at the beginning of the 1990s to a few hundred in the early 2000s. Now only very small numbers overwinter there. The reason seems to be a combination of water pollution and decreasing water level. After a period of more than 10 years, the numbers in Turkey started to increase again, and most birds are now concentrated at Manyas Lake in Western Anatolia. In 2016, the population reached a winter maximum of approximately 6,000. In the post-breeding season, up to 4,000 individuals were recorded in Eastern Anatolia in October 2014 which is far more than has ever been recorded in this season before.     

Tissue cryobanking for conservation programs: effect of tissue type and storage time after death

In this study, we investigated the temporal post-mortem limits, within which there will be guarantees of obtaining living cells from several tissues of sheep and cattle and the effect of vitrification on the ability of cells from tissue stored at different times. Muscle tissue and auricular cartilage were stored at 4°C for 5, 48, 72, 96 and 216 h post-mortem (hpm). Tissue samples were sorted into two groups: one group was in vitro cultured immediately after storage and the other was vitrified after storage and then in vitro cultured. In cattle and sheep, no differences in subconfluence rates were observed between the two experimental groups. At the same time, no significant differences were observed in the number of days required in culture to reach confluence between non-vitrified and vitrified groups when tissues were stored at 4°C for different times. In sheep, while the population doubling times (PDT) were similar in cartilage cells from vitrified and non-vitrified tissues and stored at 4°C for 5 and 216 hpm, PDT of muscle cells were longer in 216 hpm stored groups than in 5 hpm stored groups. In bovine, although the PDT of muscle cells were similar for 5 and 216 hpm and both vitrified and non-vitrified tissues and the PDT were longer in cartilage cells from vitrified than from non-vitrified tissues. In conclusion, although storage times and vitrification have different effects on tissues from cattle and sheep, this study showed that living cells could be obtained from all groups. Therefore, cartilage and muscle tissues can be stored at 4°C for 216 hpm and used for cyrobanking.     

Inhibitory effects of indole α‐lipoic acid derivatives on nitric oxide production in LPS/IFNγ activated RAW 264.7 macrophages

Alpha‐lipoic acid (α‐lipoic acid) is a potent antioxidant compound that has been shown to possess anti‐inflammatory effects. RAW 264.7 macrophages produce various inflammatory mediators such as nitric oxide, IL‐1β, IL‐6 and TNF‐alpha upon activation with LPS ( Lipopolysaccharide) and IFNγ (interferon gamma). In this study, the effect of 12 synthetic indole α‐lipoic acid derivatives on nitric oxide production and iNOS (inducible nitric oxide synthase) protein expression in LPS/IFNγ activated RAW 264.7 macrophages was determined. Cell proliferation, nitric oxide levels and iNOS protein expression were examined with thiazolyl blue tetrazolium blue test, griess assay and western blot, respectively. Our results showed that all of the indole α‐lipoic acid derivatives showed significant inhibitory effects on nitric oxide production and iNOS protein levels (p < 0.05). The most active compounds were identified as compound I‐4b, I‐4e and II‐3b. In conclusion, these indole α‐lipoic acid derivatives may have the potential for treatment of inflammatory conditions related with high nitric oxide production. Copyright © 2015 John Wiley & Sons, Ltd.     

Generation and characterization of inner photoreceptor-specific enhancer-trap lines using a novel piggyBac-Gal4 element in Drosophila

The Drosophila inner photoreceptors R7 and R8 are responsible for color vision and their differentiation starts at the third instar larval stage. Only a handful of genes with R7 or R8-cell-specific expression are known. We performed an enhancer-trap screen using a novel piggyBac transposable element, pBGay, carrying a Gal4 sequence under the control of the P promoter to identify novel genes expressed specifically in R7 or R8 cells. From this screen, three lines were analyzed in detail: piggyBac^AC109 and piggyBac^AC783 are expressed in R8 cells and piggyBac^AC887 is expressed in R7 cells at the third instar larval stage and pupal stages. Molecular analysis showed that the piggyBac elements were inserted into the first intron of CG14160 and CG7985 genes and the second intron of unzipped. We show the expression pattern in the developing eye imaginal disc, pupal retina as well as the adult retina. The photoreceptor-specific expression of these genes is reported for the first time and we propose that these lines are useful tools for studying the development of the visual system.     

Purification and characterization of intracellular and extracellular α‐glucosidases from Geobacillus toebii strain E134

Two different α‐glucosidase‐producing thermophilic E134 strains were isolated from a hot spring in Kozakli, Turkey. Based on the phenotypic, phylogenetic and chemotaxonomic evidence, the strain was proposed to be a species of G. toebii. Its thermostable exo‐α‐1,4‐glucosidases also were characterized and compared, which were purified from the intracellular and extracellular fractions with estimated molecular weights of 65 and 45 kDa. The intracellular and extracellular α‐glucosidases showed optimal activity at 65 °C, pH 7·0, and at 70 °C, pH 6·8, with 3·65 and 0·83 K_m values for the pNPG substrate, respectively. Both enzymes remained active over temperature and pH ranges of 35–70 °C and 4·5–11·0. They retained 82 and 84% of their activities when incubated at 60 °C for 5 h. Their relative activities were 45–75% and 45–60% at pH 4·5 and 11·0 values for 15 h at 35 °C. They could hydrolyse the α‐1,3 and α‐1,4 bonds on substrates in addition to a high transglycosylation activity, although the intracellular enzyme had more affinity to the substrates both in hydrolysis and transglycosylation reactions. Furthermore, although sodium dodecyl sulfate behaved as an activator for both of them at 60 °C, urea and ethanol only increased the activity of the extracellular α‐glucosidase. By this study, G. toebii E134 strain was introduced, which might have a potential in biotechnological processes when the conformational stability of its enzymes to heat, pH and denaturants were considered. Copyright © 2011 John Wiley & Sons, Ltd.     

Effects of myeloperoxidase −463 G/A gene polymorphism and plasma levels on coronary artery disease

Myeloperoxidase is a lysosomal enzyme of polymorphonuclear leucocytes that contributes to inflamatory responses. In previous studies it was shown that MPO was synthesized in atherosclerotic lesions responsible of lipoprotein oxidations. We aimed to determine the MPO −463 G/A gene polymorphism distribution in Turkish population and evaluate the effects of it on myeloperoxidase levels. There were 100 myocardial infarct patients and 100 healthy control subjects in our study. MPO polymorphism was studied by using PCR-RFLP technique and MPO levels were measured by ELISA. It was shown that MPO levels were increasing in patients after myocardial infarct event but there were no effect of MPO −463 G/A polymorphism on MPO levels. It was also found that serum total cholesterol and LDL-cholesterol levels and smoking was contributing factors in increments of MPO enzymes. We observed that MPO levels were increased in CAD but there were no effect of MPO −463 G/A polymorphism on MPO levels.     

Does resistive loading decrease diaphragmatic contractility before task failure?

While sustaining a load that leads to taskfailure, it is unclear whether diaphragmatic fatigue developsprogressively or occurs only at task failure. We hypothesized thatincremental loading produces a progressive decrease in diaphragmaticcontractility ever before task failure. Ten subjectsgenerated 60% of maximal transdiaphragmatic pressure(Pdi_max) for 2 min, 4 min, anduntil task failure. Before loading, 20 min after each period ofloading, and ~20 h after the last period of loading,Pdi_max, nonpotentiated andpotentiated Pdi twitch pressure(Pdi_tw), and the pattern of respiratory muscle recruitment during aCO₂ challenge were recorded. Sensation of inspiratory effort at the 4th min of the task-failure protocol was greater than at the same time in the preceding 4-min protocol. Surprisingly, potentiatedPdi_tw andPdi_max were reduced after 2 min ofloading and decreased further after 4 min of loading and after taskfailure; nonpotentiated Pdi_tw wasreduced after 4 min of loading and after task failure. The gastricpressure contribution to tidal breathing during aCO₂ challenge decreased progressively in relation to duration of the preceding loading period,whereas expiratory muscle recruitment progressively increased. A restperiod of ~20 h after task failure was not sufficient to normalizethese alterations in respiratory muscle recruitment or fatigue-inducedchanges in diaphragmatic contractility. In conclusion, while sustaininga mechanical load, the diaphragm progressively fatigued, ever beforetask failure, and when challenged the rib cage-to-diaphragmaticcontribution to tidal breathing and recruitment of the expiratorymuscles increased pari passu with duration of the preceding loading.

     

Differential enumeration of silage inoculants based on utilization of enzymatic activity and antibiotic sensitivity of bacteria

The differences in the composition of culture media inoculated with strains of Leuconostoc oenos were more quantitative than qualitative. Both temperature of incubation and pH significantly affected bacterial growth, the rates of substrate consumption and consequently the amount of metabolites produced. All strains degraded 5 g 1^-1 malate, except one at pH 3.5 and 25°C. Malate was metabolized before glucose except at higher pH (4.0 and 4.5) and temperature (32°C). Citrate was completely metabolized and its consumption rate was pH- and temperature-dependent. Neither acids contributed energy for growth as the Y_glu remained constant in the presence or absence of acids. There was a significant increase in fructose consumed at higher temperature. Also, the final concentration of mannitol was higher but not significantly different. The addition of acids, particularly citrate, significantly repressed mannitol formation.